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Zhang J, Yang K, Chen WQ, Sun DL, Hu HY, Li Q, Yan YS, Li YZ, Yin CH, Guo Q. SEC24D depletion induces osteogenic differentiation deficiency by inactivating the ATF6/TGF-β/Runx2 regulatory loop. Commun Biol 2025; 8:758. [PMID: 40374976 PMCID: PMC12081754 DOI: 10.1038/s42003-025-08175-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 05/06/2025] [Indexed: 05/18/2025] Open
Abstract
Protein coat complexes strongly influence intracellular cargo trafficking. Coatopathies represent a wide range of genetic conditions caused by mutations in protein coat components. The SEC24D gene, which encodes a Sec24 isoform that constitutes a cargo-specific capturer in the COPII coat, is responsible for a rare type of autosomal recessive osteogenesis imperfecta. We report an OI patient. Clinical and imaging findings suggested that the patient had OI. Genetic detection by whole-exome sequencing (WES) identified a compound heterozygous SEC24D variants, including c.2609_2610delGA (p. R870fs*10) and c.938G>A (p. R313H). In silico analysis suggested that the missense R313H mutation most likely affects protein stability and secondary structure. In vitro studies showed that knockdown or mutation of SEC24D affected the osteogenic differentiation of mesenchymal stem cells (MSCs) and inducted ER stress. Transcriptomic sequencing suggested that the TGF-β pathway mediated the destructive effect of SEC24D depletion on osteogenic differentiation. Further experiments confirmed that ATF6 participated in regulating the TGF-β pathway and osteogenic biomarkers by SEC24D. This study identified a SEC24D variation causing OI, which expanded the mutation spectrum of this gene. Further studies on the mechanism of action showed that SEC24D defects may induce osteogenic differentiation deficiency by inactivating the ATF6/TGF-β/Runx2 regulatory loop.
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Affiliation(s)
- Jing Zhang
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital; Hebei Key Laboratory of Maternal and Fetal Medicine; Shijiazhuang Key Laboratory of Reproductive Health, Shijiazhuang, Hebei, China
| | - Kai Yang
- Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Wen-Qi Chen
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital; Hebei Key Laboratory of Maternal and Fetal Medicine; Shijiazhuang Key Laboratory of Reproductive Health, Shijiazhuang, Hebei, China
| | - Dong-Lan Sun
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital; Hebei Key Laboratory of Maternal and Fetal Medicine; Shijiazhuang Key Laboratory of Reproductive Health, Shijiazhuang, Hebei, China
| | - Hua-Ying Hu
- Medical Innovation Research Division of Chinese, PLA General Hospital, Beijing, China; Jiaen Genetics Laboratory, Beijing Jiaen Hospital, Beijing, China
| | - Qian Li
- Prenatal Diagnosis Center, Department of Obstetrics and Gynaecology, Sixth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - You-Sheng Yan
- Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Ya-Zhou Li
- Department of Pediatric Orthopedic, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Cheng-Hong Yin
- Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
| | - Qing Guo
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital; Hebei Key Laboratory of Maternal and Fetal Medicine; Shijiazhuang Key Laboratory of Reproductive Health, Shijiazhuang, Hebei, China.
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Acosta-Alvear D, Harnoss JM, Walter P, Ashkenazi A. Homeostasis control in health and disease by the unfolded protein response. Nat Rev Mol Cell Biol 2025; 26:193-212. [PMID: 39501044 DOI: 10.1038/s41580-024-00794-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2024] [Indexed: 02/27/2025]
Abstract
Cells rely on the endoplasmic reticulum (ER) to fold and assemble newly synthesized transmembrane and secretory proteins - essential for cellular structure-function and for both intracellular and intercellular communication. To ensure the operative fidelity of the ER, eukaryotic cells leverage the unfolded protein response (UPR) - a stress-sensing and signalling network that maintains homeostasis by rebalancing the biosynthetic capacity of the ER according to need. The metazoan UPR can also redirect signalling from cytoprotective adaptation to programmed cell death if homeostasis restoration fails. As such, the UPR benefits multicellular organisms by preserving optimally functioning cells while removing damaged ones. Nevertheless, dysregulation of the UPR can be harmful. In this Review, we discuss the UPR and its regulatory processes as a paradigm in health and disease. We highlight important recent advances in molecular and mechanistic understanding of the UPR that enable greater precision in designing and developing innovative strategies to harness its potential for therapeutic gain. We underscore the rheostatic character of the UPR, its contextual nature and critical open questions for its further elucidation.
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Affiliation(s)
| | - Jonathan M Harnoss
- Department of General, Visceral, Thoracic and Transplant Surgery, University Hospital Giessen, Giessen, Germany
| | - Peter Walter
- Altos Labs, Inc., Bay Area Institute of Science, Redwood City, CA, USA.
| | - Avi Ashkenazi
- Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
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3
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Vašková J, Kováčová G, Pudelský J, Palenčár D, Mičková H. Methylglyoxal Formation-Metabolic Routes and Consequences. Antioxidants (Basel) 2025; 14:212. [PMID: 40002398 PMCID: PMC11852113 DOI: 10.3390/antiox14020212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/04/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Methylglyoxal (MGO), a by-product of glycolysis, plays a significant role in cellular metabolism, particularly under stress conditions. However, MGO is a potent glycotoxin, and its accumulation has been linked to the development of several pathological conditions due to oxidative stress, including diabetes mellitus and neurodegenerative diseases. This paper focuses on the biochemical mechanisms by which MGO contributes to oxidative stress, particularly through the formation of advanced glycation end products (AGEs), its interactions with antioxidant systems, and its involvement in chronic diseases like diabetes, neurodegeneration, and cardiovascular disorders. MGO exerts its effects through multiple signaling pathways, including NF-κB, MAPK, and Nrf2, which induce oxidative stress. Additionally, MGO triggers apoptosis primarily via intrinsic and extrinsic pathways, while endoplasmic reticulum (ER) stress is mediated through PERK-eIF2α and IRE1-JNK signaling. Moreover, the activation of inflammatory pathways, particularly through RAGE and NF-κB, plays a crucial role in the pathogenesis of these conditions. This study points out the connection between oxidative and carbonyl stress due to increased MGO formation, and it should be an incentive to search for a marker that could have prognostic significance or could be a targeted therapeutic intervention in various diseases.
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Affiliation(s)
- Janka Vašková
- Department of Medical Biology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 11 Košice, Slovakia
| | - Gabriela Kováčová
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik, 040 11 Košice, Slovakia; (G.K.)
| | - Jakub Pudelský
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik, 040 11 Košice, Slovakia; (G.K.)
| | - Drahomír Palenčár
- Department of Plastic Surgery, Faculty of Medicine, Comenius University Bratislava, 813 72 Bratislava, Slovakia
| | - Helena Mičková
- Department of Medical Biology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 11 Košice, Slovakia
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Gao K, Si M, Qin X, Zhang B, Wang Z, Lin P, Chen H, Wang A, Jin Y. Transcription factor XBP1s promotes endometritis-induced epithelial-mesenchymal transition by targeting MAP3K2, a key gene in the MAPK/ERK pathway. Cell Commun Signal 2025; 23:72. [PMID: 39930412 PMCID: PMC11808991 DOI: 10.1186/s12964-025-02050-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/16/2025] [Indexed: 02/14/2025] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a biological process whereby epithelial cells are transformed into cells with a mesenchymal phenotype. The transcription factor, X-box binding protein 1 splicing variant (XBP1s) is a key regulator of the endoplasmic reticulum stress response (ERS); but the function of XBP1s in the endometritis-induced EMT process remains unclear. Here we found that uterine tissues from goats with endometritis exhibited an EMT phenotype, with a significant decrease in the epithelial cell polarity marker E-cadherin and a significant increase in the mesenchymal markers N-cadherin and vimentin. We also found that sustained LPS treatment induced EMT in goat endometrial epithelial cells (gEECs), along with ERS and XBP1s overexpression. XBP1s KO significantly inhibited LPS-induced EMT and migration in gEECs, while XBP1s overexpression showed the opposite result. CUT & Tag experiments performed on XBP1s revealed that MAP3K2 was a downstream target gene for XBP1s regulation. We also found that expression of MAP3K2 was positively correlated with XBP1s expression in uterine tissues of goats with endometritis and in gEECs. Assays for dual luciferase reporter and molecular docking indicated that XBP1s protein regulated the transcription of MAP3K2 by modulating promoter activity. The knockdown of MAP3K2 expression significantly inhibited the migration and EMT of gEECs. XBP1s and MAP3K2 significantly promoted phosphorylation of p38 and ERK, activating the MAPK/ERK pathway. Treatment with the MAPK/ERK inhibitor, PD98059, reversed the effects of XBP1s and MAP3K2 overexpression on LPS-induced EMT. The MAPK/ERK activator, DHC, reversed the effects of XBP1s KO and MAP3K2 KD on EMT.
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Affiliation(s)
- Kangkang Gao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Mengqi Si
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Xinxi Qin
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Beibei Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Zongjie Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Pengfei Lin
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Huatao Chen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Aihua Wang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Yaping Jin
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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Kolapalli SP, Nielsen TM, Frankel LB. Post-transcriptional dynamics and RNA homeostasis in autophagy and cancer. Cell Death Differ 2025; 32:27-36. [PMID: 37558732 PMCID: PMC11742036 DOI: 10.1038/s41418-023-01201-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/22/2023] [Accepted: 08/01/2023] [Indexed: 08/11/2023] Open
Abstract
Autophagy is an essential recycling and quality control pathway which preserves cellular and organismal homeostasis. As a catabolic process, autophagy degrades damaged and aged intracellular components in response to conditions of stress, including nutrient deprivation, oxidative and genotoxic stress. Autophagy is a highly adaptive and dynamic process which requires an intricately coordinated molecular control. Here we provide an overview of how autophagy is regulated post-transcriptionally, through RNA processing events, epitranscriptomic modifications and non-coding RNAs. We further discuss newly revealed RNA-binding properties of core autophagy machinery proteins and review recent indications of autophagy's ability to impact cellular RNA homeostasis. From a physiological perspective, we examine the biological implications of these emerging regulatory layers of autophagy, particularly in the context of nutrient deprivation and tumorigenesis.
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Affiliation(s)
| | | | - Lisa B Frankel
- Danish Cancer Institute, Copenhagen, Denmark.
- Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
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Wilson A, McCormick C. Reticulophagy and viral infection. Autophagy 2025; 21:3-20. [PMID: 39394962 DOI: 10.1080/15548627.2024.2414424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 10/03/2024] [Accepted: 10/06/2024] [Indexed: 10/14/2024] Open
Abstract
All viruses are obligate intracellular parasites that use host machinery to synthesize viral proteins. In infected eukaryotes, viral secreted and transmembrane proteins are synthesized at the endoplasmic reticulum (ER). Many viruses refashion ER membranes into bespoke factories where viral products accumulate while evading host pattern recognition receptors. ER processes are tightly regulated to maintain cellular homeostasis, so viruses must either conform to ER regulatory mechanisms or subvert them to ensure efficient viral replication. Reticulophagy is a catabolic process that directs lysosomal degradation of ER components. There is accumulating evidence that reticulophagy serves as a form of antiviral defense; we call this defense "xERophagy" to acknowledge its relationship to xenophagy, the catabolic degradation of microorganisms by macroautophagy/autophagy. In turn, viruses can subvert reticulophagy to suppress host antiviral responses and support efficient viral replication. Here, we review the evidence for functional interplay between viruses and the host reticulophagy machinery.Abbreviations: AMFR: autocrine motility factor receptor; ARF4: ADP-ribosylation factor 4; ARL6IP1: ADP-ribosylation factor-like 6 interacting protein 1; ATL3: atlastin GTPase 3; ATF4: activating transcription factor 4; ATF6: activating transcription factor 6; BPIFB3: BPI fold containing family B, member 3; CALCOCO1: calcium binding and coiled coil domain 1; CAMK2B: calcium/calmodulin-dependent protein kinase II, beta; CANX: calnexin; CDV: canine distemper virus; CCPG1: cell cycle progression 1; CDK5RAP3/C53: CDK5 regulatory subunit associated protein 3; CIR: cargo-interacting region; CoV: coronavirus; CSNK2/CK2: casein kinase 2; CVB3: coxsackievirus B3; DAPK1: death associated protein kinase 1; DENV: dengue virus; DMV: double-membrane vesicles; EBOV: Ebola virus; EBV: Epstein-Barr Virus; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EMCV: encephalomyocarditis virus; EMV: extracellular microvesicle; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signalling 1; EV: extracellular vesicle; EV71: enterovirus 71; FIR: RB1CC1/FIP200-interacting region; FMDV: foot-and-mouth disease virus; HCMV: human cytomegalovirus; HCV: hepatitis C virus; HMGB1: high mobility group box 1; HSPA5/BiP: heat shock protein 5; IFN: interferon; IFNG/IFN-γ: interferon gamma; KSHV: Kaposi's sarcoma-associated herpesvirus; LIR: MAP1LC3/LC3-interacting region; LNP: lunapark, ER junction formation factor; MAP1LC3: microtubule-associated protein 1 light chain 3; MAP3K5/ASK1: mitogen-activated protein kinase kinase kinase 5; MAPK/JNK: mitogen-activated protein kinase; MeV: measles virus; MHV: murine hepatitis virus; NS: non-structural; PDIA3: protein disulfide isomerase associated 3; PRR: pattern recognition receptor; PRRSV: porcine reproductive and respiratory syndrome virus; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RETREG1/FAM134B: reticulophagy regulator 1; RHD: reticulon homology domain; RTN3: reticulon 3; RTN3L: reticulon 3 long; sAIMs: shuffled Atg8-interacting motifs; SARS-CoV: severe acute respiratory syndrome coronavirus; SINV: Sindbis virus; STING1: stimulator of interferon response cGAMP interactor 1; SVV: Seneca Valley virus; SV40: simian virus 40; TEX264: testis expressed gene 264 ER-phagy receptor; TFEB: transcription factor EB; TRAF2: TNF receptor-associated factor 2; UIM: ubiquitin-interacting motif; UFM1: ubiquitin-fold modifier 1; UPR: unfolded protein response; VAPA: vesicle-associated membrane protein, associated protein A; VAPB: vesicle-associated membrane protein, associated protein B and C; VZV: varicella zoster virus; WNV: West Nile virus; XBP1: X-box binding protein 1; XBP1s: XBP1 spliced; xERophagy: xenophagy involving reticulophagy; ZIKV: Zika virus.
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Affiliation(s)
- Alexa Wilson
- Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Craig McCormick
- Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
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Joshi AS, Castillo MB, Tomaz da Silva M, Vuong AT, Gunaratne PH, Darabi R, Liu Y, Kumar A. Single-nucleus transcriptomic analysis reveals the regulatory circuitry of myofiber XBP1 during regenerative myogenesis. iScience 2024; 27:111372. [PMID: 39650729 PMCID: PMC11625362 DOI: 10.1016/j.isci.2024.111372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 10/04/2024] [Accepted: 11/08/2024] [Indexed: 12/11/2024] Open
Abstract
Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is activated in skeletal muscle under multiple conditions. However, the role of the UPR in the regulation of muscle regeneration remains less understood. We demonstrate that gene expression of various markers of the UPR is induced in both myogenic and non-myogenic cells in regenerating muscle. Genetic ablation of X-box binding protein 1 (XBP1), a downstream target of the Inositol requiring enzyme 1α (IRE1α) arm of the UPR, in myofibers attenuates muscle regeneration in adult mice. Single nucleus RNA sequencing (snRNA-seq) analysis showed that deletion of XBP1 in myofibers perturbs proteolytic systems and mitochondrial function in myogenic cells. Trajectory analysis of snRNA-seq dataset showed that XBP1 regulates the abundance of satellite cells and the formation of new myofibers in regenerating muscle. In addition, ablation of XBP1 disrupts the composition of non-myogenic cells in injured muscle microenvironment. Collectively, our study suggests that myofiber XBP1 regulates muscle regeneration through both cell-autonomous and -non-autonomous mechanisms.
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Affiliation(s)
- Aniket S. Joshi
- Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, TX 77204, USA
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA
| | - Micah B. Castillo
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
| | - Meiricris Tomaz da Silva
- Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, TX 77204, USA
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA
| | - Anh Tuan Vuong
- Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, TX 77204, USA
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA
| | - Preethi H. Gunaratne
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
| | - Radbod Darabi
- Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, TX 77204, USA
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA
| | - Yu Liu
- Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, TX 77204, USA
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
| | - Ashok Kumar
- Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, TX 77204, USA
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA
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Li W, Liu J, Yu T, Lu F, Miao Q, Meng X, Xiao W, Yang H, Zhang X. ZDHHC9-mediated Bip/GRP78 S-palmitoylation inhibits unfolded protein response and promotes bladder cancer progression. Cancer Lett 2024; 598:217118. [PMID: 39002690 DOI: 10.1016/j.canlet.2024.217118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 07/07/2024] [Accepted: 07/09/2024] [Indexed: 07/15/2024]
Abstract
Recent studies have highlighted palmitoylation, a novel protein post-translational modification, as a key player in various signaling pathways that contribute to tumorigenesis and drug resistance. Despite this, its role in bladder cancer (BCa) development remains inadequately understood. In this study, ZDHHC9 emerged as a significantly upregulated oncogene in BCa. Functionally, ZDHHC9 knockdown markedly inhibited tumor proliferation, promoted tumor cell apoptosis, and enhanced the efficacy of gemcitabine (GEM) and cisplatin (CDDP). Mechanistically, SP1 was found to transcriptionally activate ZDHHC9 expression. ZDHHC9 subsequently bound to and palmitoylated the Bip protein at cysteine 420 (Cys420), thereby inhibiting the unfolded protein response (UPR). This palmitoylation at Cys420 enhanced Bip's protein stability and preserved its localization within the endoplasmic reticulum (ER). ZDHHC9 might become a novel therapeutic target for BCa and could also contribute to combination therapy with GEM and CDDP.
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Affiliation(s)
- Weiquan Li
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China
| | - Jingchong Liu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China
| | - Tiexi Yu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China
| | - Feiyi Lu
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China
| | - Qi Miao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China
| | - Xiangui Meng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China.
| | - Wen Xiao
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China.
| | - Hongmei Yang
- Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Xiaoping Zhang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China.
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Hu Q, Zhang L, Tao Y, Xie S, Wang A, Luo C, Yang R, Shen Z, He B, Fang Y, Chen P. Semaglutide Ameliorates Hepatocyte Steatosis in a Cell Co-Culture System by Downregulating the IRE1α-XBP1-C/EBPα Signaling Pathway in Macrophages. Pharmacology 2024; 110:26-35. [PMID: 39089233 DOI: 10.1159/000540654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 07/25/2024] [Indexed: 08/03/2024]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is currently the most common type of chronic liver disease. Semaglutide is a glucose-lowering drug administered for the treatment of type 2 diabetes mellitus (T2DM) and is clinically effective in the treatment of NAFLD. X-box binding protein 1 (XBP1) is related to the pathogenesis of both NAFLD and T2DM. The aim of the present study was to demonstrate whether the underlying mechanism of semaglutide treatment for NAFLD is via downregulation of the inositol-requiring transmembrane kinase/endonuclease-1α (IRE1α)-XBP1-CCAAT/enhancer binding protein α (C/EBPα) signaling pathway in macrophages. METHODS In the present study, NAFLD cell modeling was induced by oleic acid (0.4 mm) and palmitic acid (0.2 mm). Hepatocytes (AML12) and macrophages (RAW264.7) were co-cultured in 6-well Transwell plates. Semaglutide (60 or 140 nm) was administrated for 24 h, while pioglitazone (2 μm) and toyocamycin (200 nm) were used as a positive control drug and a XBP1 inhibitor, respectively. Autophagy and apoptosis of AML12 cells were detected by transmission electron microscopy and Western blotting (WB). Hepatocyte steatosis was evaluated by adopting total intracellular triglyceride determination, analysis of the relative expression of proteins and genes associated with lipid metabolism and hepatocyte Oil red O staining. Detection of inflammation factors was conducted by ELISA and WB. To explore the underlying mechanism of NAFLD treatment with semaglutide, the relative expression of related proteins and genes were tested. RESULTS Our study demonstrated that semaglutide treatment improved autophagy and inhibited apoptosis of hepatocytes, while notably ameliorating steatosis of hepatocytes. In addition, inflammation was attenuated in the NAFLD cell co-culture model after semaglutide administration. Semaglutide also significantly reduced the protein and gene expression levels of the IRE1α-XBP1-C/EBPα signaling pathway in macrophages. CONCLUSION Semaglutide partially ameliorated NAFLD by downregulating the IRE1α-XBP1-C/EBPα signaling pathway in macrophages. These findings may provide a potential theoretical basis for semaglutide therapy for NAFLD.
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Affiliation(s)
- Qin Hu
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
- Department of Endocrinology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Li Zhang
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
| | - YiTing Tao
- Department of Nephrology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - ShuangLin Xie
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
| | - AiYun Wang
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
| | - Caiying Luo
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
| | - RenHua Yang
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
| | - Zhiqiang Shen
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
| | - Bo He
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
| | - Yu Fang
- Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Peng Chen
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming, China
- College of Modern Biomedical Industry, Kunming Medical University, Kunming, China
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10
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Wang J, Fan P, Shen P, Fan C, Zhao P, Yao Shen, Dong K, Ling R, Chen S, Zhang J. XBP1s activates METTL3/METTL14 for ER-phagy and paclitaxel sensitivity regulation in breast cancer. Cancer Lett 2024; 596:216846. [PMID: 38582397 DOI: 10.1016/j.canlet.2024.216846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 03/25/2024] [Accepted: 03/31/2024] [Indexed: 04/08/2024]
Abstract
Cancer cells employ the unfolded protein response (UPR) or induce autophagy, especially selective removal of certain ER domains via reticulophagy (termed ER-phagy), to mitigate endoplasmic reticulum (ER) stress for ER homeostasis when encountering microenvironmental stress. N6-methyladenosine (m6A) is one of the most abundant epitranscriptional modifications and plays important roles in various biological processes. However, the molecular mechanism of m6A modification in the ER stress response is poorly understood. In this study, we first found that ER stress could dramatically elevate m6A methylation levels through XBP1s-dependent transcriptional upregulation of METTL3/METTL14 in breast cancer (BC) cells. Further MeRIP sequencing and relevant validation results confirmed that ER stress caused m6A methylation enrichment on target genes for ER-phagy. Mechanistically, METTL3/METTL14 increased ER-phagy machinery formation by promoting m6A modification of the ER-phagy regulators CALCOCO1 and p62, thus enhancing their mRNA stability. Of note, we further confirmed that the chemotherapeutic drug paclitaxel (PTX) could induce ER stress and increase m6A methylation for ER-phagy. Furthermore, the combination of METTL3/METTL14 inhibitors with PTX demonstrated a significant synergistic therapeutic effect in both BC cells and xenograft mice. Thus, our data built a novel bridge on the crosstalk between ER stress, m6A methylation and ER-phagy. Most importantly, our work provides novel evidence of METTL3 and METTL14 as potential therapeutic targets for PTX sensitization in breast cancer.
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Affiliation(s)
- Jiajia Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Pengyu Fan
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Peng Shen
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Cong Fan
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Pan Zhao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Yao Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Kewei Dong
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Rui Ling
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Suning Chen
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Jian Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China.
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11
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Qian Q, Li M, Zhang Z, Davis SW, Rahmouni K, Norris AW, Cao H, Ding WX, Hotamisligil GS, Yang L. Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression. Cell Metab 2024; 36:1550-1565.e9. [PMID: 38718793 PMCID: PMC11222033 DOI: 10.1016/j.cmet.2024.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 03/05/2024] [Accepted: 04/17/2024] [Indexed: 07/05/2024]
Abstract
Obesity alters levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, dysregulation of which leads to nonalcoholic fatty liver disease (NAFLD). However, the impact of obesity on intra-pituitary homeostasis is largely unknown. Here, we uncovered a blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice and humans. Furthermore, we found that obesity inflames the pituitary gland, leading to impaired pituitary inositol-requiring enzyme 1α (IRE1α)-X-box-binding protein 1 (XBP1) UPR branch, which is essential for protecting against pituitary endocrine defects and NAFLD progression. Intriguingly, pituitary IRE1-deletion resulted in hypothyroidism and suppressed the thyroid hormone receptor B (THRB)-mediated activation of Xbp1 in the liver. Conversely, activation of the hepatic THRB-XBP1 axis improved NAFLD in mice with pituitary UPR defect. Our study provides the first evidence and mechanism of obesity-induced intra-pituitary cellular defects and the pathophysiological role of pituitary-liver UPR communication in NAFLD progression.
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Affiliation(s)
- Qingwen Qian
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Mark Li
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Zeyuan Zhang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Shannon W Davis
- Department of Biological Sciences, College of Arts and Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Kamal Rahmouni
- Department of Neuroscience and Pharmacology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Andrew W Norris
- Division of Endocrinology and Diabetes, Department of Pediatrics, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Huojun Cao
- Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA 52242, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Gökhan S Hotamisligil
- Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
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12
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Wang T, Wang D, Kuang G, Gong X, Zhang L, Wan J, Li K. Derlin-1 promotes diet-induced non-alcoholic fatty liver disease via increasing RIPK3-mediated necroptosis. Free Radic Biol Med 2024; 217:29-47. [PMID: 38522486 DOI: 10.1016/j.freeradbiomed.2024.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/29/2024] [Accepted: 03/15/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND & AIMS Unrestricted endoplasmic reticulum (ER) stress and the continuous activation of ER associated protein degradation (ERAD) pathway might lead to the aggravation of non-alcoholic steatohepatitis (NASH). Derlin-1 has been considered to be an integral part of the ERAD pathway, which is involved in the regulation of the transport and excretion of protein degradation products within ER. However, the regulatory role and mechanism of Derlin-1 in NASH remains unclear. METHODS The expression of Derlin-1 was firstly detected in the liver of normal and NASH animal model and patient. Then, western diet (WD)-induced NASH mice were administrated with the lentivirus-mediated Derlin-1 knockdown or overexpression. Finally, RIPK3 knockout mice were used to explore the mechanism. The liver injury, hepatic steatosis, inflammation, and fibrosis as well as ER stress signal pathway were evaluated. RESULTS The levels of Derlin-1 were significantly elevated in the liver of WD-fed mice and NASH patients when compared to the control group. Furthermore, Derlin-1 knockdown attenuated WD-induced liver injury, lipid accumulation, inflammatory response, and fibrosis. Conversely, overexpression of Derlin-1 presented the completely opposite results. Mechanistically, Derlin-1 enhanced ER stress pathways and led to necroptosis, and RIPK3 knockout dramatically reduced Derlin-1 expression and reversed the progression of NASH aggravated by Derlin-1. CONCLUSIONS Notably, Derlin-1 is a critical modulator in NASH. It may accelerate the progression of NASH by regulating the activation of the ERAD pathway and further aggravating the ER stress, which might be involved in RIPK3-mediated necroptosis. Therefore, targeting Derlin-1 as a novel intervention point holds the potential to delay or even reverse NASH.
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Affiliation(s)
- Ting Wang
- Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Dehua Wang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Ge Kuang
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China.
| | - Xia Gong
- Department of Anatomy, Chongqing Medical University, Chongqing, China.
| | - Li Zhang
- Department of Ophthalmology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Jingyuan Wan
- Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China; Department of Pharmacology, Chongqing Medical University, Chongqing, China.
| | - Ke Li
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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13
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Dashti Z, Yousefi Z, Kiani P, Taghizadeh M, Maleki MH, Borji M, Vakili O, Shafiee SM. Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth. Metabolism 2024; 154:155811. [PMID: 38309690 DOI: 10.1016/j.metabol.2024.155811] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/23/2024] [Accepted: 01/28/2024] [Indexed: 02/05/2024]
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is on the rise, mirroring a global surge in diabetes and metabolic syndrome, as its major leading causes. NAFLD represents a spectrum of liver disorders, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Mechanistically, we know the unfolded protein response (UPR) as a protective cellular mechanism, being triggered under circumstances of endoplasmic reticulum (ER) stress. The hepatic UPR is turned on in a broad spectrum of liver diseases, including NAFLD. Recent data also defines molecular mechanisms that may underlie the existing correlation between UPR activation and NAFLD. More interestingly, subsequent studies have demonstrated an additional mechanism, i.e. autophagy, to be involved in hepatic steatosis, and thus NAFLD pathogenesis, principally by regulating the insulin sensitivity, hepatocellular injury, innate immunity, fibrosis, and carcinogenesis. All these findings suggest possible mechanistic roles for autophagy in the progression of NAFLD and its complications. Both UPR and autophagy are dynamic and interconnected fluxes that act as protective responses to minimize the harmful effects of hepatic lipid accumulation, as well as the ER stress during NAFLD. The functions of UPR and autophagy in the liver, together with findings of decreased hepatic autophagy in correlation with conditions that predispose to NAFLD, such as obesity and aging, suggest that autophagy and UPR, alone or combined, may be novel therapeutic targets against the disease. In this review, we discuss the current evidence on the interplay between autophagy and the UPR in connection to the NAFLD pathogenesis.
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Affiliation(s)
- Zahra Dashti
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zeynab Yousefi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pouria Kiani
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Motahareh Taghizadeh
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hasan Maleki
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Borji
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Sayed Mohammad Shafiee
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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14
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Metcalf MG, Monshietehadi S, Sahay A, Durieux J, Frakes AE, Velichkovska M, Mena C, Farinas A, Sanchez M, Dillin A. Cell non-autonomous control of autophagy and metabolism by glial cells. iScience 2024; 27:109354. [PMID: 38500817 PMCID: PMC10946330 DOI: 10.1016/j.isci.2024.109354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 11/01/2023] [Accepted: 02/23/2024] [Indexed: 03/20/2024] Open
Abstract
Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, and longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.
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Affiliation(s)
- Melissa G. Metcalf
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Samira Monshietehadi
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Arushi Sahay
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Jenni Durieux
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Ashley E. Frakes
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Martina Velichkovska
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Cesar Mena
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Amelia Farinas
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Melissa Sanchez
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Andrew Dillin
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA
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15
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Settembre C, Perera RM. Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology. Nat Rev Mol Cell Biol 2024; 25:223-245. [PMID: 38001393 DOI: 10.1038/s41580-023-00676-x] [Citation(s) in RCA: 65] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2023] [Indexed: 11/26/2023]
Abstract
Every cell must satisfy basic requirements for nutrient sensing, utilization and recycling through macromolecular breakdown to coordinate programmes for growth, repair and stress adaptation. The lysosome orchestrates these key functions through the synchronised interplay between hydrolytic enzymes, nutrient transporters and signalling factors, which together enable metabolic coordination with other organelles and regulation of specific gene expression programmes. In this Review, we discuss recent findings on lysosome-dependent signalling pathways, focusing on how the lysosome senses nutrient availability through its physical and functional association with mechanistic target of rapamycin complex 1 (mTORC1) and how, in response, the microphthalmia/transcription factor E (MiT/TFE) transcription factors exert feedback regulation on lysosome biogenesis. We also highlight the emerging interactions of lysosomes with other organelles, which contribute to cellular homeostasis. Lastly, we discuss how lysosome dysfunction contributes to diverse disease pathologies and how inherited mutations that compromise lysosomal hydrolysis, transport or signalling components lead to multi-organ disorders with severe metabolic and neurological impact. A deeper comprehension of lysosomal composition and function, at both the cellular and organismal level, may uncover fundamental insights into human physiology and disease.
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Affiliation(s)
- Carmine Settembre
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
| | - Rushika M Perera
- Department of Anatomy, University of California at San Francisco, San Francisco, CA, USA.
- Department of Pathology, University of California at San Francisco, San Francisco, CA, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
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16
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Chen H, Gong S, Zhang H, Chen Y, Liu Y, Hao J, Liu H, Li X. From the regulatory mechanism of TFEB to its therapeutic implications. Cell Death Discov 2024; 10:84. [PMID: 38365838 PMCID: PMC10873368 DOI: 10.1038/s41420-024-01850-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/01/2024] [Accepted: 02/05/2024] [Indexed: 02/18/2024] Open
Abstract
Transcription factor EB (TFEB), known as a major transcriptional regulator of the autophagy-lysosomal pathway, regulates target gene expression by binding to coordinated lysosomal expression and regulation (CLEAR) elements. TFEB are regulated by multiple links, such as transcriptional regulation, post-transcriptional regulation, translational-level regulation, post-translational modification (PTM), and nuclear competitive regulation. Targeted regulation of TFEB has been victoriously used as a treatment strategy in several disease models such as ischemic injury, lysosomal storage disorders (LSDs), cancer, metabolic disorders, neurodegenerative diseases, and inflammation. In this review, we aimed to elucidate the regulatory mechanism of TFEB and its applications in several disease models by targeting the regulation of TFEB as a treatment strategy.
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Affiliation(s)
- Huixia Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Siqiao Gong
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Hongyong Zhang
- Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhan-jiang Central Hospital, Zhanjiang, 524001, China
| | - Yongming Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yonghan Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Junfeng Hao
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Huafeng Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Xiaoyu Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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17
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Ren Q, Sun Q, Fu J. Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease. Autophagy 2024; 20:221-241. [PMID: 37700498 PMCID: PMC10813589 DOI: 10.1080/15548627.2023.2254191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
ABBREVIATIONS ACOX1: acyl-CoA oxidase 1; ADH5: alcohol dehydrogenase 5 (class III), chi polypeptide; ADIPOQ: adiponectin, C1Q and collagen domain containing; ATG: autophagy related; BECN1: beclin 1; CRTC2: CREB regulated transcription coactivator 2; ER: endoplasmic reticulum; F2RL1: F2R like trypsin receptor 1; FA: fatty acid; FOXO1: forkhead box O1; GLP1R: glucagon like peptide 1 receptor; GRK2: G protein-coupled receptor kinase 2; GTPase: guanosine triphosphatase; HFD: high-fat diet; HSCs: hepatic stellate cells; HTRA2: HtrA serine peptidase 2; IRGM: immunity related GTPase M; KD: knockdown; KDM6B: lysine demethylase 6B; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LAP: LC3-associated phagocytosis; LDs: lipid droplets; Li KO: liver-specific knockout; LSECs: liver sinusoidal endothelial cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MED1: mediator complex subunit 1; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NFE2L2: NFE2 like bZIP transcription factor 2; NOS3: nitric oxide synthase 3; NR1H3: nuclear receptor subfamily 1 group H member 3; OA: oleic acid; OE: overexpression; OSBPL8: oxysterol binding protein like 8; PA: palmitic acid; RUBCNL: rubicon like autophagy enhancer; PLIN2: perilipin 2; PLIN3: perilipin 3; PPARA: peroxisome proliferator activated receptor alpha; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; RAB: member RAS oncogene family; RPTOR: regulatory associated protein of MTOR complex 1; SCD: stearoyl-CoA desaturase; SIRT1: sirtuin 1; SIRT3: sirtuin 3; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1;SREBF2: sterol regulatory element binding transcription factor 2; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; TAGs: triacylglycerols; TFEB: transcription factor EB; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VMP1: vacuole membrane protein 1.
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Affiliation(s)
- Qiannan Ren
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Qiming Sun
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junfen Fu
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
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18
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Guan L, Guo L, Zhang H, Liu H, Zhou W, Zhai Y, Yan X, Men X, Peng L. Naringin Protects against Non-Alcoholic Fatty Liver Disease by Promoting Autophagic Flux and Lipophagy. Mol Nutr Food Res 2024; 68:e2200812. [PMID: 38054638 DOI: 10.1002/mnfr.202200812] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 05/07/2023] [Indexed: 12/07/2023]
Abstract
The autophagic degradation of lipid droplets, termed lipophagy, is the main mechanism contributing to lipid consumption in hepatocytes. Identifying effective and safe natural compounds that target lipophagy to eliminate excess lipids may be a potential therapeutic strategy for non-alcoholic fatty liver disease (NAFLD). Here the effects of naringin on NAFLD and the underlying mechanisms involved are investigated. Naringin treatment effectively relieves HFD-induced hepatic steatosis in mice and inhibits PA-induced lipid accumulation in hepatocytes. Increased p62 and LC3-II levels are observed with excess lipid support autophagosome accumulation and impaired autophagic flux. Treatment with naringin restores TFEB-mediated lysosomal biogenesis, thereby promoting the fusion of autophagosomes and lysosomes, restoring impaired autophagic flux and further inducing lipophagy. However, the knockdown of TFEB in hepatocytes or the hepatocyte-specific knockout of TFEB in mice abrogates naringin-induced lipophagy, eliminating its therapeutic effect on hepatic steatosis. These results demonstrate that TFEB-mediated lysosomal biogenesis and subsequent lipophagy play essential roles in the ability of naringin to mitigate hepatic steatosis and suggest that naringin is a promising drug for treating NAFLD.
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Affiliation(s)
- Lingling Guan
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063000, China
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100000, China
- The fifth affiliated hospital, Guangzhou Medical University, Guangzhou, 510000, China
| | - Lan Guo
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063000, China
| | - Heng Zhang
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063000, China
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100000, China
| | - Hao Liu
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100000, China
| | - Wenling Zhou
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100000, China
| | - Yuanyuan Zhai
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100000, China
| | - Xu Yan
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100000, China
| | - Xiuli Men
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063000, China
| | - Liang Peng
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Medical Science, China-Japan Friendship Hospital, Beijing, 100000, China
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19
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Li X, Pan Y, Liu K, Yang Y, Ye Y, Xu Q, Fan M, Guo F. Identification and functional coordination analysis of gene co-expression networks in different tissues of XBP1 cartilage-specific deficient mice. Cell Signal 2024; 113:110929. [PMID: 37875231 DOI: 10.1016/j.cellsig.2023.110929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 09/21/2023] [Accepted: 10/14/2023] [Indexed: 10/26/2023]
Abstract
Abnormal differentiation and proliferation of chondrocytes leads to various diseases related to growth and development. The process of chondrocyte differentiation involves a series of complex cellular and molecular interactions. X-box binding protein 1 (XBP1), an essential molecule of the unfolded protein response (UPR) in Endoplasmic Reticulum (ER) stress, participated in cartilage development and causes other related diseases. We previously reported that XBP1 deficiency in cartilage impacts the function and associated diseases of many different tissues including cartilage. However, how differential expression of genes modulates the roles of cartilage and other tissues when XBP1 is lack of in chondrocytes remains unclear. We aimed to screen for differentially expressed (DE) genes in cartilage, brain, heart, and muscle by high-throughput sequencing in XBP1 cartilage-specific knockout (CKO) mice. Further, gene co-expression networks were constructed by weighted gene co-expression network analysis (WGCNA) algorithm and pivot genes were identified in the above four tissues. Protein detection, Hematoxylin-eosin (HE) staining and immunohistochemistry (IHC) experiments have proved that these differentially co-expressed genes participate in the downstream regulatory pathway of different tissues and affect tissue function.Significantly differentially expressed mRNAs [differentially expressed genes (DEGs)] were identified between XBP1 CKO mice and controls in cartilage, brain, heart, and muscle tissues, including 610, 126, 199 and 219 DEGs, respectively. 39 differentially co-expressed genes were identified in the above four tissues, and they were important pivot genes. Comprehensive analysis discovered that XBP1 deficiency in cartilage influences the difference of co-expressed genes between cartilage and other different tissues. These differentially co-expressed genes participate in downstream regulatory pathways of different tissues and affect tissue functions. Collectively, our conclusions may contribute potential biomarkers and molecular mechanisms for the mutual modulation between cartilage and different tissues and the diagnosis and treatment of diseases caused by abnormalities in different tissues. The analysis also provides meaningful insights for future genetic discoveries.
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Affiliation(s)
- Xiaoli Li
- Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yiming Pan
- Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Kaiwen Liu
- Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yuyou Yang
- Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yuanlan Ye
- Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Qingbo Xu
- School of Cardiovascular Medicine and Sciences, King's College London BHF Centre, London, United Kingdom
| | - Mengtian Fan
- Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Fengjin Guo
- Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
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20
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Chao X, Niu M, Wang S, Ma X, Yang X, Sun H, Hu X, Wang H, Zhang L, Huang R, Xia M, Ballabio A, Jaeschke H, Ni HM, Ding WX. High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice. Acta Pharm Sin B 2024; 14:190-206. [PMID: 38261809 PMCID: PMC10793101 DOI: 10.1016/j.apsb.2023.10.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 01/25/2024] Open
Abstract
Macroautophagy (referred to as autophagy hereafter) is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles. Previous studies showed that autophagy protects against acetaminophen (APAP)-induced injury (AILI) via selective removal of damaged mitochondria and APAP protein adducts. The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes. In the present study, we showed that transcription factor EB (TFEB), a master transcription factor for lysosomal biogenesis, was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers. Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI, respectively. Mechanistically, overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2 (NRF2) activation to protect against AILI. We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists. Among these agonists, salinomycin, an anticoccidial and antibacterial agent, activated TFEB and protected against AILI in mice. In conclusion, genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Mengwei Niu
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Xiaowen Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Xiao Yang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Hua Sun
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Xujia Hu
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hua Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei 230032, China
| | - Li Zhang
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ruili Huang
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
| | - Menghang Xia
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA
| | - Andrea Ballabio
- Telethon Institute of Genetics and Medicine, TIGEM, Pozzuoli, Naples 80131, Italy
- Medical Genetics, Department of Translational Medicine, Federico II University, Naples 80131, Italy
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Internal Medicine, Division of Gastroenterology, Hepatology & Motility, University of Kansas Medical Center, Kansas City, KS 66160, USA
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21
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Wu LX, Tan XY, Xu YC, Zheng H, Wei XL, Lv WH, Luo Z. SIRT1-NRF2-TFEB axis-mediated hepatic lipophagy alleviates the lipid deposition induced by high glucose in yellow catfish Pelteobagrus fulvidraco. Comp Biochem Physiol B Biochem Mol Biol 2024; 269:110894. [PMID: 37597585 DOI: 10.1016/j.cbpb.2023.110894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/16/2023] [Accepted: 08/16/2023] [Indexed: 08/21/2023]
Abstract
Metabolic stress induces lipophagy, a crucial process in lipid catabolism, which is under the regulation of autophagy involving transcription factor EB (TFEB). However, the precise mechanisms underlying TFEB's control remain enigmatic. In this study, we focused on yellow catfish (Pelteobagrus fulvidraco) as the model to investigate lipophagy activation under high glucose-induced lipid deposition. We hypothesized that lipophagy mediates high glucose-induced lipid deposition and proposed the involvement of the SIRT1-NRF2-TFEB pathway in the activation of lipophagy. We found that there was a functional antioxidative responsive element (ARE) on the tfeb gene promoter; high glucose (HG) increased the nuclear translocation of nuclear factor E2-related factor 2 (NRF2) recruitment to the tfeb promoter; TFEB, whose expression is regulated by NRF2, mediated the HG-induced activation of lipophagy and lipolysis. Moreover, we found that HG increased the silencing information regulator 2 related enzymes 1 (SIRT1) expression, and that the SIRT1 mediates NRF2 translocation to the nucleus, increased TFEB expression and activated autophagy. In the glucose tolerance test, blood glucose increased rapidly and plateaued at 4-h glucose after injection and then declined until 48-h post-injection. Generally speaking, the transcript level and protein expression of SIRT1, NRF2, TFEB, microtubule-associated proteins 1A/1B light chain 3B (LC3B), and autophagy-related 6 (Beclin1) showed similar trend after glucose injection, and trends to increase and plateau at 4-h injection, then decline until 16-h post-injection, and finally increased until 48-h post-injection. These results indicated that the SIRT1-NRF2-TFEB axis-mediated lipophagy may be an adaptive response to glucose injection. Collectively, for the first time, we found that NRF2 was associated directly with TFEB-mediated transcriptional control of hepatic lipophagy, and that lipophagy helps to alleviate the HG-induced lipid deposition via SIRT1-NRF2-TFEB activation in yellow catfish.
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Affiliation(s)
- Li-Xiang Wu
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiao-Ying Tan
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Yi-Chuang Xu
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Hua Zheng
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Xiao-Lei Wei
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Wu-Hong Lv
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhi Luo
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agricultural University, Wuhan 430070, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
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22
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Wang Z, Lei Z, Wang Q, Jiang Q, Zhang Z, Liu X, Xing B, Li S, Guo X, Liu Y, Li X, Qi Y, Shu K, Zhang H, Huang Y, Lei T. Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma. Int J Biol Sci 2024; 20:801-817. [PMID: 38169563 PMCID: PMC10758099 DOI: 10.7150/ijbs.86736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 12/10/2023] [Indexed: 01/05/2024] Open
Abstract
Somatostatin analogues (SSTA) are first-line pharmacological treatment choice for acromegaly, which received satisfying tumor shrinkage and normalization of growth hormone. However, there are still patients unresponsive to SSTA, and the underline mechanism remains unknown. Besides, there is no evidence regarding the role of endoplasmic reticulum stress (ERS) and its transmission in SSTA resistance, which also require investigation. Primary growth hormone adenoma cells and cell lines were treated with SSTA; autophagy double-labeled LC3 (mRFP-GFP) adenovirus transfection, flow cytometry sorting, western blotting, calcium imaging as well as immunofluorescence staining were used to determine ERS and autophagy signal transmission; xenograft and syngeneic tumor in vivo model were exploited to confirm the ERS signal transmission mediated effect. Our results revealed that SSTA induces ERS in pituitary growth hormone (GH) adenoma cells. The ERS signals can be intercellularly transmitted, leading to less responsible to SSTA treatment. Moreover, SSTA stimulates inositol triphosphate (IP3) elevation, mediating ERS intercellular transfer. In addition, connexin 36 tunnels ERS transmission, and its blocker, Quinine, exhibits a synergistic effect with SSTA treating GH adenoma. Our study provided insight into ERS intercellular transmission mediated SSTA resistance, which could be translated into clinical usage to improve SSTA efficiency in GH adenoma treatment.
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Affiliation(s)
- Zihan Wang
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhuowei Lei
- Department of Orthopedics, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Quanji Wang
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qian Jiang
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhuo Zhang
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaojin Liu
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Biao Xing
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sihan Li
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiang Guo
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yanchao Liu
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xingbo Li
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yiwei Qi
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Kai Shu
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huaqiu Zhang
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yimin Huang
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ting Lei
- Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China
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23
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Sachan V, Le Dévéhat M, Roubtsova A, Essalmani R, Laurendeau JF, Garçon D, Susan-Resiga D, Duval S, Mikaeeli S, Hamelin J, Evagelidis A, Chong M, Paré G, Chernetsova E, Gao ZH, Robillard I, Ruiz M, Trinh VQH, Estall JL, Faraj M, Austin RC, Sauvageau M, Prat A, Kiss RS, Seidah NG. PCSK7: A novel regulator of apolipoprotein B and a potential target against non-alcoholic fatty liver disease. Metabolism 2024; 150:155736. [PMID: 37967646 DOI: 10.1016/j.metabol.2023.155736] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 10/17/2023] [Accepted: 11/08/2023] [Indexed: 11/17/2023]
Abstract
BACKGROUND Epidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. We associated the known PCSK7 gain-of-function non-coding SNP rs236918 with higher levels of plasma apolipoprotein B (apoB) and the loss-of-function coding variant p.Pro777Leu (SNP rs201598301) with lower apoB and TG. Herein, we aimed to unravel the in vivo role of liver PCSK7. METHODS We biochemically defined the functional role of PCSK7 in lipid metabolism using hepatic cell lines and Pcsk7-/- mice. Our findings were validated following subcutaneous administration of hepatocyte-targeted N-acetylgalactosamine (GalNAc)-antisense oligonucleotides (ASOs) against Pcsk7. RESULTS Independent of its proteolytic activity, membrane-bound PCSK7 binds apoB100 in the endoplasmic reticulum and enhances its secretion. Mechanistically, the loss of PCSK7/Pcsk7 leads to apoB100 degradation, triggering an unfolded protein response, autophagy, and β-oxidation, eventually reducing lipid accumulation in hepatocytes. Non-alcoholic fatty liver disease (NAFLD) was induced by a 12-week high fat/fructose/cholesterol diet in wild type (WT) and Pcsk7-/- mice that were then allowed to recover on a 4-week control diet. Pcsk7-/- mice recovered more effectively than WT mice from all NAFLD-related liver phenotypes. Finally, subcutaneous administration of GalNAc-ASOs targeting hepatic Pcsk7 to WT mice validated the above results. CONCLUSIONS Our data reveal hepatic PCSK7 as one of the major regulators of apoB, and its absence reduces apoB secretion from hepatocytes favoring its ubiquitination and degradation by the proteasome. This results in a cascade of events, eventually reducing hepatic lipid accumulation, thus supporting the notion of silencing PCSK7 mRNA in hepatocytes for targeting NAFLD.
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Affiliation(s)
- Vatsal Sachan
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Maïlys Le Dévéhat
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Anna Roubtsova
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Rachid Essalmani
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Jean-Francois Laurendeau
- RNA and Noncoding Mechanisms of Disease, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Damien Garçon
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Delia Susan-Resiga
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Stéphanie Duval
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Sahar Mikaeeli
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Josée Hamelin
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Alexandra Evagelidis
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Michael Chong
- Department of Biochemistry & Biomedical Sciences, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
| | - Guillaume Paré
- Department of Biochemistry & Biomedical Sciences, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
| | | | - Zu-Hua Gao
- Department of Pathology, McGill University Health Centre, Montréal, QC, Canada
| | - Isabelle Robillard
- Montreal Heart Institute, Metabolomics Platform, Montreal, Quebec, Canada; Department of Nutrition, Université de Montréal, Montréal, QC, Canada
| | - Matthieu Ruiz
- Montreal Heart Institute, Metabolomics Platform, Montreal, Quebec, Canada; Department of Nutrition, Université de Montréal, Montréal, QC, Canada
| | - Vincent Quoc-Huy Trinh
- Departement of Pathology and Cellular Biology, Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montréal, QC, Canada
| | - Jennifer L Estall
- Molecular Mechanisms of Diabetes, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - May Faraj
- Nutrition Department, Université de Montréal, Research Unit on Nutrition, Lipoproteins and Cardiometabolic Diseases, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada
| | - Richard C Austin
- Department of Medicine, Division of Nephrology, McMaster University, The Research Institute of St. Joe's Hamilton and the Hamilton Center for Kidney Research, Hamilton, ON, Canada
| | - Martin Sauvageau
- RNA and Noncoding Mechanisms of Disease, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Annik Prat
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada
| | - Robert S Kiss
- McGill University Health Centre Research Institute, Montréal, QC, Canada
| | - Nabil G Seidah
- Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montréal, QC, Canada.
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24
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Zhou QM, Zheng L. Research progress on the relationship between Paneth cells-susceptibility genes, intestinal microecology and inflammatory bowel disease. World J Clin Cases 2023; 11:8111-8125. [PMID: 38130785 PMCID: PMC10731169 DOI: 10.12998/wjcc.v11.i34.8111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/26/2023] [Accepted: 11/27/2023] [Indexed: 12/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a disorder of the immune system and intestinal microecosystem caused by environmental factors in genetically susceptible people. Paneth cells (PCs) play a central role in IBD pathogenesis, especially in Crohn's disease development, and their morphology, number and function are regulated by susceptibility genes. In the intestine, PCs participate in the formation of the stem cell microenvironment by secreting antibacterial particles and play a role in helping maintain the intestinal microecology and intestinal mucosal homeostasis. Moreover, PC proliferation and maturation depend on symbiotic flora in the intestine. This paper describes the interactions among susceptibility genes, PCs and intestinal microecology and their effects on IBD occurrence and development.
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Affiliation(s)
- Qi-Ming Zhou
- Department of Nephrology, Lanxi Hospital of Traditional Chinese Medicine, Lanxi 321100, Zhejiang Province, China
| | - Lie Zheng
- Department of Gastroenterology, Shaanxi Hospital of Traditional Chinese Medicine, Xi’an 710003, Shaanxi Province, China
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Wen W, Zheng H, Li W, Huang G, Chen P, Zhu X, Cao Y, Li J, Huang X, Huang Y. Transcription factor EB: A potential integrated network regulator in metabolic-associated cardiac injury. Metabolism 2023; 147:155662. [PMID: 37517793 DOI: 10.1016/j.metabol.2023.155662] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/19/2023] [Accepted: 07/21/2023] [Indexed: 08/01/2023]
Abstract
With the worldwide pandemic of metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), cardiometabolic disease (CMD) has become a significant cause of death in humans. However, the pathophysiology of metabolic-associated cardiac injury is complex and not completely clear, and it is important to explore new strategies and targets for the treatment of CMD. A series of pathophysiological disturbances caused by metabolic disorders, such as insulin resistance (IR), hyperglycemia, hyperlipidemia, mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress (ERS), autophagy dysfunction, calcium homeostasis imbalance, and endothelial dysfunction, may be related to the incidence and development of CMD. Transcription Factor EB (TFEB), as a transcription factor, has been extensively studied for its role in regulating lysosomal biogenesis and autophagy. Recently, the regulatory role of TFEB in other biological processes, including the regulation of glucose homeostasis, lipid metabolism, etc. has been gradually revealed. In this review, we will focus on the relationship between TFEB and IR, lipid metabolism, endothelial dysfunction, oxidative stress, inflammation, ERS, calcium homeostasis, autophagy, and mitochondrial quality control (MQC) and the potential regulatory mechanisms among them, to provide a comprehensive summary for TFEB as a potential new therapeutic target for CMD.
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Affiliation(s)
- Weixing Wen
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China
| | - Haoxiao Zheng
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China.
| | - Weiwen Li
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China
| | - Guolin Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China
| | - Peng Chen
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China
| | - Xiaolin Zhu
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China.
| | - Yue Cao
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China
| | - Jiahuan Li
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China
| | - Xiaohui Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China
| | - Yuli Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China; The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation Research, Guangzhou, China; Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), NO. 1 Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong 528308, China.
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Wikan N, Tocharus J, Oka C, Sivasinprasasn S, Chaichompoo W, Denlumpai P, Suksamrarn A, Tocharus C. Pelargonic acid vanillylamide alleviates hepatic autophagy and ER stress in hepatic steatosis model. Food Chem Toxicol 2023; 180:113987. [PMID: 37611858 DOI: 10.1016/j.fct.2023.113987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/24/2023] [Accepted: 08/11/2023] [Indexed: 08/25/2023]
Abstract
Pelargonic acid vanillylamide (PAVA) has been shown to reduce hepatic lipid accumulation in an obese rat model, however the underlying mechanism responsible for regulating lipid metabolism remains unclear. This study investigated the molecular mechanisms invoked by PAVA in regulating lipogenesis, autophagy, and endoplasmic reticulum (ER) stress in obese rats. Male Sprague-Dawley rats were fed on a diet consisting of 65.26% fat (16 weeks) and HepG2 cells were incubated with 200 μM oleic acid (OA) plus 100 μM palmitic acid (PA) for 48 h. These treatments resulted in a steatosis model. PAVA was shown to reduce fat deposition in hepatocytes in HepG2 by reducing lipotoxicity, the triglyceride content, the expression of sterol regulatory element binding protein 1c (SREBP-1c) and fatty acid synthase (FASN). PAVA also significantly reduced the calcium level and the expression of calpain 2 and upregulated the expression of Atg7 in comparison to the HFD group. In addition, PAVA was shown to significantly decrease the expression of autophagy pathway-related proteins including LC3 and p62. Treatment with PAVA (1 mg/day) reduced the expressions of ER stress markers Bip, ATF6 (p50), p-IRE1/IRE1, p-eIF2α/eIF2α, pJNK, CHOP and cleaved CASP12. In conclusion, PAVA ameliorated obesity induced hepatic steatosis by attenuating defective autophagy and ER stress pathways.
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Affiliation(s)
- Naruemon Wikan
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chio Oka
- Laboratory of Functional Genomics and Medicine, Division of Biological Science, Nara Institute of Science and Technology, Nara, Japan
| | | | - Waraluck Chaichompoo
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Panida Denlumpai
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Radiation Research and Medical Imaging, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
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Li Y, Li K, Pan T, Xie Q, Cheng Y, Wu X, Xu R, Liu X, Liu L, Gao J, Yuan W, Qu X, Cui S. Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca 2+ER perturbation in hepatocellular carcinoma. Acta Pharm Sin B 2023; 13:3744-3755. [PMID: 37719369 PMCID: PMC10501870 DOI: 10.1016/j.apsb.2023.05.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/05/2023] [Accepted: 05/06/2023] [Indexed: 09/19/2023] Open
Abstract
The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rβ is translocated into the ER by β-arrestin2 (β-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβ levels. ER IGF-1Rβ phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rβ with SERCA2, and therefore ER IGF-1Rβ failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rβ and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.
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Affiliation(s)
- Yanan Li
- Department of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Keqin Li
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Ting Pan
- Department of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Qiaobo Xie
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Yuyao Cheng
- Department of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Xinfeng Wu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Rui Xu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Xiaohui Liu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Li Liu
- Department of Pharmacology, Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China
| | - Jiangming Gao
- Department of Pharmacology, Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China
| | - Wenmin Yuan
- Department of Pharmacology, Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China
| | - Xianjun Qu
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Shuxiang Cui
- Department of Toxicology and Sanitary Chemistry, Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing 100069, China
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Lv J, Zhang R, Li D, Liu Y. Resveratrol plays an anti-fibrotic and anti-autophagy role by stimulating miR-192-5p expression in urethral fibrosis. Funct Integr Genomics 2023; 23:241. [PMID: 37450096 DOI: 10.1007/s10142-023-01173-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/25/2023] [Accepted: 07/09/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND Resveratrol (RSV) exerts anti-fibrotic effects on various fibrotic diseases. Whereas the biological role of RSV on urethral fibrosis remains to be elucidated. This study aimed to determine the mechanisms by which RSV affects urethral fibrosis and autophagy. METHODS Sprague‒Dawley rats and primary fibroblasts were treated with transforming growth factor-β1 (TGFβ1) to generate in vivo and in vitro fibrosis models. Then, those were treated with RSV, and autophagy and fibrosis-related indicators were tested. RESULTS Firstly, we found that RSV reversed the upregulation of indicators related to TGFβ1-induced fibrosis (TGFβ1, α-smooth muscle actin, collagen type I, and collagen type III), autophagy (TFEB and LC3), and TGFβR1/Smad4 pathway, as well as the downregulation of p62 and miR-192-5p expression both in vivo and in vitro. Overexpression of miR-192-5p suppressed the upregulation of fibrosis-related markers expression, as well as TFEB and LC3 expression, induced by TGFβ1, while the expression trend of p62 was the opposite. Inhibiting miR-192-5p reversed the effects of RSV on the model group cells. It was also shown that RSV combined with sh-Smad4 inhibited autophagy more effectively than RSV alone. CONCLUSION These results suggest that RSV inhibits urinary fibrosis and autophagy via the miR-192-5p/TGFβR1/Smad4 pathway. RAV may be a potential drug for alleviating urethral fibrosis.
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Affiliation(s)
- Jin Lv
- Hunan Traditional Chinese Medical College, Zhuzhou, China
| | - Rui Zhang
- Hunan Traditional Chinese Medical College, Zhuzhou, China
| | - DaoYuan Li
- Department of Urology, Hainan Afliated Hospital of Hainan Medical University, Haikou, China
- Department of Urology, Hainan General Hospital, Haikou, China
| | - Yan Liu
- Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, China.
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Dang TT, Kim MJ, Lee YY, Le HT, Kim KH, Nam S, Hyun SH, Kim HL, Chung SW, Chung HT, Jho EH, Yoshida H, Kim K, Park CY, Lee MS, Back SH. Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress. Autophagy 2023; 19:2111-2142. [PMID: 36719671 PMCID: PMC10283430 DOI: 10.1080/15548627.2023.2173900] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 02/01/2023] Open
Abstract
There are diverse links between macroautophagy/autophagy pathways and unfolded protein response (UPR) pathways under endoplasmic reticulum (ER) stress conditions to restore ER homeostasis. Phosphorylation of EIF2S1/eIF2α is an important mechanism that can regulate all three UPR pathways through transcriptional and translational reprogramming to maintain cellular homeostasis and overcome cellular stresses. In this study, to investigate the roles of EIF2S1 phosphorylation in regulation of autophagy during ER stress, we used EIF2S1 phosphorylation-deficient (A/A) cells in which residue 51 was mutated from serine to alanine. A/A cells exhibited defects in several steps of autophagic processes (such as autophagosome and autolysosome formation) that are regulated by the transcriptional activities of the autophagy master transcription factors TFEB and TFE3 under ER stress conditions. EIF2S1 phosphorylation was required for nuclear translocation of TFEB and TFE3 during ER stress. In addition, EIF2AK3/PERK, PPP3/calcineurin-mediated dephosphorylation of TFEB and TFE3, and YWHA/14-3-3 dissociation were required for their nuclear translocation, but were insufficient to induce their nuclear retention during ER stress. Overexpression of the activated ATF6/ATF6α form, XBP1s, and ATF4 differentially rescued defects of TFEB and TFE3 nuclear translocation in A/A cells during ER stress. Consequently, overexpression of the activated ATF6 or TFEB form more efficiently rescued autophagic defects, although XBP1s and ATF4 also displayed an ability to restore autophagy in A/A cells during ER stress. Our results suggest that EIF2S1 phosphorylation is important for autophagy and UPR pathways, to restore ER homeostasis and reveal how EIF2S1 phosphorylation connects UPR pathways to autophagy.Abbreviations: A/A: EIF2S1 phosphorylation-deficient; ACTB: actin beta; Ad-: adenovirus-; ATF6: activating transcription factor 6; ATZ: SERPINA1/α1-antitrypsin with an E342K (Z) mutation; Baf A1: bafilomycin A1; BSA: bovine serum albumin; CDK4: cyclin dependent kinase 4; CDK6: cyclin dependent kinase 6; CHX: cycloheximide; CLEAR: coordinated lysosomal expression and regulation; Co-IP: coimmunoprecipitation; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; DAPI: 4',6-diamidino-2-phenylindole dihydrochloride; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; DTT: dithiothreitol; EBSS: Earle's Balanced Salt Solution; EGFP: enhanced green fluorescent protein; EIF2S1/eIF2α: eukaryotic translation initiation factor 2 subunit alpha; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERAD: endoplasmic reticulum-associated degradation; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FBS: fetal bovine serum; gRNA: guide RNA; GSK3B/GSK3β: glycogen synthase kinase 3 beta; HA: hemagglutinin; Hep: immortalized hepatocyte; IF: immunofluorescence; IRES: internal ribosome entry site; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LMB: leptomycin B; LPS: lipopolysaccharide; MAP1LC3A/B/LC3A/B: microtubule associated protein 1 light chain 3 alpha/beta; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEFs: mouse embryonic fibroblasts; MFI: mean fluorescence intensity; MTORC1: mechanistic target of rapamycin kinase complex 1; NES: nuclear export signal; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; OE: overexpression; PBS: phosphate-buffered saline; PLA: proximity ligation assay; PPP3/calcineurin: protein phosphatase 3; PTM: post-translational modification; SDS: sodium dodecyl sulfate; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SEM: standard error of the mean; TEM: transmission electron microscopy; TFE3: transcription factor E3; TFEB: transcription factor EB; TFs: transcription factors; Tg: thapsigargin; Tm: tunicamycin; UPR: unfolded protein response; WB: western blot; WT: wild-type; Xbp1s: spliced Xbp1; XPO1/CRM1: exportin 1.
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Affiliation(s)
- Thao Thi Dang
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea
| | - Mi-Jeong Kim
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea
| | - Yoon Young Lee
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 44919, Korea
| | - Hien Thi Le
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea
| | - Kook Hwan Kim
- Severance Biomedical Research Institute, Yonsei University College of Medicine, 03722, Seoul, Korea
| | - Somi Nam
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea
| | - Seung Hwa Hyun
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea
| | - Hong Lim Kim
- Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su Wol Chung
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea
| | - Hun Taeg Chung
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea
| | - Eek-Hoon Jho
- Department of Life Science, University of Seoul, Seoul, Korea
| | - Hiderou Yoshida
- Department of Molecular Biochemistry, Graduate School of Life Science, University of Hyogo, 678-1297, Hyogo, Japan
| | - Kyoungmi Kim
- Department of Biomedical Sciences and Department of Physiology, Korea University College of Medicine, 02841, Seoul, Korea
| | - Chan Young Park
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 44919, Korea
| | - Myung-Shik Lee
- Department of Integrated Biomedical Science & Division of Endocrinology, Department of Internal Medicine, SIMS (Soonchunhyang Institute of Medi-bio Science) & Soonchunhyang University Hospital, Soonchunhyang University, 31151, Cheonan, Korea
| | - Sung Hoon Back
- School of Biological Sciences, University of Ulsan, Ulsan, 44610, Korea
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30
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Li Z, Ouyang H, Zhu J. Traditional Chinese medicines and natural products targeting immune cells in the treatment of metabolic-related fatty liver disease. Front Pharmacol 2023; 14:1195146. [PMID: 37361209 PMCID: PMC10289001 DOI: 10.3389/fphar.2023.1195146] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/30/2023] [Indexed: 06/28/2023] Open
Abstract
MAFLD stands for metabolic-related fatty liver disease, which is a prevalent liver disease affecting one-third of adults worldwide, and is strongly associated with obesity, hyperlipidemia, and type 2 diabetes. It encompasses a broad spectrum of conditions ranging from simple liver fat accumulation to advanced stages like chronic inflammation, tissue damage, fibrosis, cirrhosis, and even hepatocellular carcinoma. With limited approved drugs for MAFLD, identifying promising drug targets and developing effective treatment strategies is essential. The liver plays a critical role in regulating human immunity, and enriching innate and adaptive immune cells in the liver can significantly improve the pathological state of MAFLD. In the modern era of drug discovery, there is increasing evidence that traditional Chinese medicine prescriptions, natural products and herb components can effectively treat MAFLD. Our study aims to review the current evidence supporting the potential benefits of such treatments, specifically targeting immune cells that are responsible for the pathogenesis of MAFLD. By providing new insights into the development of traditional drugs for the treatment of MAFLD, our findings may pave the way for more effective and targeted therapeutic approaches.
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Cao R, Tian H, Zhang Y, Liu G, Xu H, Rao G, Tian Y, Fu X. Signaling pathways and intervention for therapy of type 2 diabetes mellitus. MedComm (Beijing) 2023; 4:e283. [PMID: 37303813 PMCID: PMC10248034 DOI: 10.1002/mco2.283] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 06/13/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID-19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.
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Affiliation(s)
- Rong Cao
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Huimin Tian
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yu Zhang
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Geng Liu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Haixia Xu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Guocheng Rao
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yan Tian
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Xianghui Fu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
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32
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Piell KM, Petri BJ, Head KZ, Wahlang B, Xu R, Zhang X, Pan J, Rai SN, de Silva K, Chariker JH, Rouchka EC, Tan M, Li Y, Cave MC, Klinge CM. Disruption of the mouse liver epitranscriptome by long-term aroclor 1260 exposure. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 100:104138. [PMID: 37137421 PMCID: PMC10330322 DOI: 10.1016/j.etap.2023.104138] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/26/2023] [Accepted: 04/29/2023] [Indexed: 05/05/2023]
Abstract
Chronic environmental exposure to polychlorinated biphenyls (PCBs) is associated with non-alcoholic fatty liver disease (NAFLD) and exacerbated by a high fat diet (HFD). Here, chronic (34 wks.) exposure of low fat diet (LFD)-fed male mice to Aroclor 1260 (Ar1260), a non-dioxin-like (NDL) mixture of PCBs, resulted in steatohepatitis and NAFLD. Twelve hepatic RNA modifications were altered with Ar1260 exposure including reduced abundance of 2'-O-methyladenosine (Am) and N(6)-methyladenosine (m6A), in contrast to increased Am in the livers of HFD-fed, Ar1260-exposed mice reported previously. Differences in 13 RNA modifications between LFD- and HFD- fed mice, suggest that diet regulates the liver epitranscriptome. Integrated network analysis of epitranscriptomic modifications identified a NRF2 (Nfe2l2) pathway in the chronic, LFD, Ar1260-exposed livers and an NFATC4 (Nfatc4) pathway for LFD- vs. HFD-fed mice. Changes in protein abundance were validated. The results demonstrate that diet and Ar1260 exposure alter the liver epitranscriptome in pathways associated with NAFLD.
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Affiliation(s)
- Kellianne M Piell
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Belinda J Petri
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Kimberly Z Head
- University of Louisville Hepatobiology and Toxicology Center, USA
| | - Banrida Wahlang
- University of Louisville Hepatobiology and Toxicology Center, USA
| | - Raobo Xu
- University of Louisville Hepatobiology and Toxicology Center, USA; Department of Chemistry, University of Louisville College of Arts and Sciences, USA
| | - Xiang Zhang
- University of Louisville Hepatobiology and Toxicology Center, USA; Department of Chemistry, University of Louisville College of Arts and Sciences, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA
| | - Jianmin Pan
- Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Cancer Data Science Center, Biostatistics and Informatics Shared Resource, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Shesh N Rai
- Division of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Cancer Data Science Center, Biostatistics and Informatics Shared Resource, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Kalpani de Silva
- KY INBRE Bioinformatics Core, University of Louisville, Louisville, KY 40292, USA; Department of Neuroscience Training, University of Louisville, Louisville, KY 40292, USA
| | - Julia H Chariker
- KY INBRE Bioinformatics Core, University of Louisville, Louisville, KY 40292, USA; Department of Neuroscience Training, University of Louisville, Louisville, KY 40292, USA
| | - Eric C Rouchka
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA; KY INBRE Bioinformatics Core, University of Louisville, Louisville, KY 40292, USA
| | - Min Tan
- Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Yan Li
- Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Matthew C Cave
- University of Louisville Hepatobiology and Toxicology Center, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA; The University of Louisville Superfund Research Center, USA
| | - Carolyn M Klinge
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA.
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Liu X, Li X, Su S, Yuan Y, Liu W, Zhu M, Zheng Q, Zeng X, Fu F, Lu Y, Chen Y. Oleic acid improves hepatic lipotoxicity injury by alleviating autophagy dysfunction. Exp Cell Res 2023:113655. [PMID: 37253404 DOI: 10.1016/j.yexcr.2023.113655] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/19/2023] [Accepted: 05/21/2023] [Indexed: 06/01/2023]
Abstract
Lipotoxicity caused by excess free fatty acids, particularly saturated fatty acids (SFAs) such as palmitic acid (PA), is one of the most important pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, unsaturated fatty acids (UFAs), such as oleic acid (OA), are nontoxic and can combat SFA-induced toxicity through alleviation of cell apoptosis, endoplasmic reticulum stress (ER stress) and lipids metabolism disorder. However, whether OA is able to regulate autophagy is largely unknown. So, this study aims to investigate the mechanism underlying OA mediated modulation of autophagy in hepatocytes and mice with NAFLD. In vitro, human hepatoma cell line HepG2 cells, human normal liver cells L-02 and mouse normal liver cells AML12 were treated with palmitic acid (PA)/tunicamycin (TM) or/and OA for 48 h. In vivo, C57/BL6 mice were fed with high fat diet (HFD) to induce NAFLD. And the HFD was partial replaced by olive oil to observe the protective effects of olive oil. We demonstrated that PA/TM impaired cell viability and induced cellular apoptosis in HepG2 cells and L-02 cells. Moreover, PA/TM induced autophagy impairment by reducing the nuclear translocation of transcription factor EB (TFEB) and inhibiting the activity of CTSB. However, OA substantially alleviated PA/TM induced cellular apoptosis and autophagy dysfunction in hepatocytes. Additionally, restoring autophagy function is able to reduce ER stress. Similarly, HFD for 20 weeks successfully established NAFLD model in C57/BL6 mice, and significant autophagy impairment were observed in liver tissues. Noteworthily, 30% replacement of HFD with olive oil had profoundly reversed NAFLD. It significantly impoved steatosis, and reduced autophagy dysfunction, ER stress and apoptosis in liver tissue. Conclusively, these data demonstrated that OA is able to effectively impove autophagy dysfunction under the context of both PA and ER stress inducer induced lipotoxicity, and OA mediated regulation of lysosome dysfunction through TFEB plays an important role, suggesting that the regulation of ER stress-autophagy axis is a critical mechanism in OA driven protection in NAFLD.
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Affiliation(s)
- Xiaohong Liu
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Xiaoyu Li
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Shan Su
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Yujia Yuan
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Wen Liu
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Min Zhu
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Qing Zheng
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Xin Zeng
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Fudong Fu
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China
| | - Yanrong Lu
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China
| | - Younan Chen
- Department of Clinical Nutrition and Key Laboratory of Transplant Engineering and Immunology, NHFPC, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, PR China; Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China.
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Gwon MA, Kim MJ, Kang HG, Joo YE, Jeon SB, Jeong PS, Kim SU, Sim BW, Koo DB, Song BS. Cadmium exposure impairs oocyte meiotic maturation by inducing endoplasmic reticulum stress in vitro maturation of porcine oocytes. Toxicol In Vitro 2023; 91:105615. [PMID: 37207789 DOI: 10.1016/j.tiv.2023.105615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/04/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
Cadmium (Cd) is toxic metal that can induce various diseases, such as cardiovascular, nervous, and reproductive systems. This study investigated the effect of Cd exposure on porcine oocyte maturation and the underlying mechanism. Porcine cumulus-oocyte complexes were exposed various Cd concentration and tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum (ER) stress during in vitro maturation (IVM). After IVM, we evaluated meiotic maturation, ER stress, and oocyte quality by Cd exposure. Cd exposure inhibited cumulus cell expansion and meiotic maturation, increased oocyte degeneration, and induced ER stress. The levels of spliced XBP1 and ER stress-associated transcripts, markers of ER stress, were elevated in Cd-treated cumulus-oocyte complexes and denuded oocytes during IVM. Moreover, Cd-induced ER stress impaired oocyte quality by disrupting mitochondrial function and elevating intracellular reactive oxygen species levels while decreasing ER function. Interestingly, TUDCA supplementation significantly decreased the expression of ER stress-related genes and increased the quantity of ER compared with the Cd treatment. Additionally, TUDCA was also able to rescue excessive levels of ROS and restore normal mitochondrial function. Moreover, the addition of TUDCA under Cd exposure greatly ameliorated Cd-mediated detrimental effects on meiotic maturation and oocyte quality, including cumulus cell expansion and MII rate. These findings suggest that Cd exposure during IVM impairs the meiotic maturation of oocytes by inducing of ER stress.
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Affiliation(s)
- Min-Ah Gwon
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea; Department of Biotechnology, Daegu University, Gyeongsangbuk-do 38453, Republic of Korea
| | - Min Ju Kim
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea
| | - Hyo-Gu Kang
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea
| | - Ye Eun Joo
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea
| | - Se-Been Jeon
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea
| | - Pil-Soo Jeong
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea
| | - Sun-Uk Kim
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea; Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34113, Republic of Korea
| | - Bo-Woong Sim
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea
| | - Deog-Bon Koo
- Department of Biotechnology, Daegu University, Gyeongsangbuk-do 38453, Republic of Korea.
| | - Bong-Seok Song
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Chungcheongbuk-do 28116, Republic of Korea.
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Ulaganathan T, Perales S, Mani S, Baskhairoun BA, Rajasingh J. Pathological implications of cellular stress in cardiovascular diseases. Int J Biochem Cell Biol 2023; 158:106397. [PMID: 36931385 PMCID: PMC10124590 DOI: 10.1016/j.biocel.2023.106397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 03/10/2023] [Accepted: 03/14/2023] [Indexed: 03/17/2023]
Abstract
Cellular stress has been a key factor in the development of cardiovascular diseases. Major types of cellular stress such as mitochondrial stress, endoplasmic reticulum stress, hypoxia, and replicative stress have been implicated in clinical complications of cardiac patients. The heart is the central regulator of the body by supplying oxygenated blood throughout the system. Impairment of cellular function could lead to heart failure, myocardial infarction, ischemia, and even stroke. Understanding the effect of these distinct types of cellular stress on cardiac function is crucial for the scientific community to understand and develop novel therapeutic approaches. This review will comprehensively explain the different mechanisms of cellular stress and the most recent findings related to stress-induced cardiac dysfunction.
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Affiliation(s)
- Thennavan Ulaganathan
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Biotechnology, SRM Institute of Science and Technology, kattankulathur, Tamilnadu, 603203, India
| | - Selene Perales
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Saiprahalad Mani
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Biotechnology, SRM Institute of Science and Technology, kattankulathur, Tamilnadu, 603203, India
| | - Boula A Baskhairoun
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Johnson Rajasingh
- Department of Bioscience Research, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Medicine-Cardiology, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
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Niu Z, Tang G, Wang X, Yang X, Zhao Y, Wang Y, Liu Q, Zhang F, Zhao Y, Ding X, Hao X. Trigonochinene E promotes lysosomal biogenesis and enhances autophagy via TFEB/TFE3 in human degenerative NP cells against oxidative stress. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 112:154720. [PMID: 36868108 DOI: 10.1016/j.phymed.2023.154720] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 02/01/2023] [Accepted: 02/15/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Macroautophagy (henceforth autophagy) is the major form of autophagy, which delivers intracellular cargo to lysosomes for degradation. Considerable research has revealed that the impairment of lysosomal biogenesis and autophagic flux exacerbates the development of autophagy-related diseases. Therefore, reparative medicines restoring lysosomal biogenesis and autophagic flux in cells may have therapeutic potential against the increasing prevalence of these diseases. PURPOSE The aim of the present study was thus to explore the effect of trigonochinene E (TE), an aromatic tetranorditerpene isolated from Trigonostemon flavidus, on lysosomal biogenesis and autophagy and to elucidate the potential underlying mechanism. METHODS Four human cell lines, HepG2, nucleus pulposus (NP), HeLa and HEK293 cells were applied in this study. The cytotoxicity of TE was evaluated by MTT assay. Lysosomal biogenesis and autophagic flux induced by 40 μM TE were analyzed using gene transfer techniques, western blotting, real-time PCR and confocal microscopy. Immunofluorescence, immunoblotting and pharmacological inhibitors/activators were applied to determine the changes in the protein expression levels in mTOR, PKC, PERK, and IRE1α signaling pathways. RESULTS Our results showed that TE promotes lysosomal biogenesis and autophagic flux by activating the transcription factors of lysosomes, transcription factor EB (TFEB) and transcription factor E3 (TFE3). Mechanistically, TE induces TFEB and TFE3 nuclear translocation through an mTOR/PKC/ROS-independent and endoplasmic reticulum (ER) stress-mediated pathway. The PERK and IRE1α branches of ER stress are crucial for TE-induced autophagy and lysosomal biogenesis. Whereas TE activated PERK, which mediated calcineurin dephosphorylation of TFEB/TFE3, IRE1α was activated and led to inactivation of STAT3, which further enhanced autophagy and lysosomal biogenesis. Functionally, knockdown of TFEB or TFE3 impairs TE-induced lysosomal biogenesis and autophagic flux. Furthermore, TE-induced autophagy protects NP cells from oxidative stress to ameliorate intervertebral disc degeneration (IVDD). CONCLUSIONS Here, our study showed that TE can induce TFEB/TFE3-dependent lysosomal biogenesis and autophagy via the PERK-calcineurin axis and IRE1α-STAT3 axis. Unlike other agents regulating lysosomal biogenesis and autophagy, TE showed limited cytotoxicity, thereby providing a new direction for therapeutic opportunities to use TE to treat diseases with impaired autophagy-lysosomal pathways, including IVDD.
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Affiliation(s)
- Zhenpeng Niu
- School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China; Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Guihua Tang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Xuenan Wang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China; Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Xu Yang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Yueqin Zhao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Yinyuan Wang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China; School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China
| | - Qin Liu
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, Guizhou 550014, China
| | - Fan Zhang
- Department of Orthopedics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Yuhan Zhao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
| | - Xiao Ding
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China; Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing 100730, China.
| | - Xiaojiang Hao
- School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550025, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany Chinese Academy of Sciences, Kunming, Yunnan 650201, China; Research Unit of Chemical Biology of Natural Anti-Virus Products, Chinese Academy of Medical Sciences, Beijing 100730, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang, Guizhou 550014, China.
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Zhu Y, Zhang Y, Fan Z, Fang Y, Zheng Y, Li Y, Yang M, Guo C, Li Y, Zhou X, Sun Z, Wang J. Silica Nanoparticles Trigger Chaperone HSPB8-Assisted Selective Autophagy via TFEB Activation in Hepatocytes. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2204310. [PMID: 36464658 DOI: 10.1002/smll.202204310] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 11/22/2022] [Indexed: 06/17/2023]
Abstract
Silica nanoparticles (SiNPs) are one of the most common inorganic nanomaterials. Autophagy is the predominant biological response to nanoparticles and transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway. Previous studies show that SiNPs induce autophagosome accumulation, yet the precise underlying mechanisms remain uncertain. The present study investigates the role of TFEB during SiNP-induced autophagy. SiNP-induced TFEB nuclear translocation is verified using immunofluorescence and western blot assay. The regulation of TFEB is proved to be via EIF2AK3 pathway. A TFEB knockout (KO) cell line is constructed to validate the TFEB involvement in SiNP-induced autophagy. The transcriptomes of wild-type and TFEB KO cells are compared using RNA-sequencing to identify genes of the TFEB-mediated autophagy and lysosome pathways affected by SiNPs. Based on these data and the Human Autophagy Database, four candidate autophagic genes are identified, including HSPB8, ATG4D, CTSB and CTSD. Specifically, that the chaperone HSPB8 is upregulated through SiNP-mediated TFEB activation and forms a chaperone-assisted selective autophagy (CASA) complex with BAG3 and HSC70, triggering HSPB8-assisted selective autophagy, is found. Thus, this study characterizes a novel mechanism underlying SiNP-induced autophagy that helps pave the way for further research on the toxicity and risk assessment of SiNPs.
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Affiliation(s)
- Ye Zhu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Yukang Zhang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Zhuying Fan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Yuting Fang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Yucao Zheng
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Yang Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Man Yang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Caixia Guo
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Yanbo Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Xianqing Zhou
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
| | - Ji Wang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, P. R. China
- Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, P. R. China
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Qi M, Jiang Q, Yang S, Zhang C, Liu J, Liu W, Lin P, Chen H, Zhou D, Tang K, Wang A, Jin Y. The endoplasmic reticulum stress-mediated unfolded protein response protects against infection of goat endometrial epithelial cells by Trueperella pyogenes via autophagy. Virulence 2022; 13:122-136. [PMID: 34967271 PMCID: PMC9794013 DOI: 10.1080/21505594.2021.2021630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Trueperella pyogenes is an important bacterial pathogen of a wide range of domestic and wild animals. Autophagy plays a key role in eliminating T. pyogenes in a process that is dependent on mechanistic target of rapamycin (mTOR). The endoplasmic reticulum (ER) stress response also is critical for autophagy regulation. However, the relationship between ER stress and T. pyogenes is uncharacterized and the intracellular survival mechanisms of T. pyogenes have not been investigated adequately. In this study, we show that T. pyogenes invades goat endometrial epithelial cells (gEECs). Meanwhile, we observed that GRP78 was upregulated significantly, and that unfolded protein response (UPR) also were activated after infection. Additionally, treatment with activators and inhibitors of ER stress downregulated and upregulated, respectively, intracellular survival of T. pyogenes. Blocking the three arms of the UPR pathway separately enhanced T. pyogenes survival and inflammatory reaction to different levels. We also show that LC3-labeled autophagosomes formed around the invading T. pyogenes and that autolysosome-like vesicles were visible in gEECs using transmission electron microscopy. Moreover, tunicamycin did not inhibit the intracellular survival of T. pyogenes under conditions in which autophagy was blocked. Finally, severe challenge with T. pyogenes induced host cell apoptosis which also may indicate a role for ER stress in the infection response. In summary, we demonstrate here that ER stress and UPR are novel modulators of autophagy that inhibit T. pyogenes intracellular survival in gEECs, which has the potential to be developed as an effective therapeutic target in T. pyogenes infectious disease.
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Affiliation(s)
- Maozhen Qi
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Qingran Jiang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Siwei Yang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Chenxi Zhang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Jianguo Liu
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Wei Liu
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Pengfei Lin
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Huatao Chen
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Dong Zhou
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Keqiong Tang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Aihua Wang
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China
| | - Yaping Jin
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&f University, Yanglin, Shaanxi, China,CONTACT Yaping Jin
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Kobara M, Toba H, Nakata T. Roles of autophagy in angiotensin II-induced cardiomyocyte apoptosis. Clin Exp Pharmacol Physiol 2022; 49:1342-1351. [PMID: 36059129 DOI: 10.1111/1440-1681.13719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 08/25/2022] [Accepted: 09/01/2022] [Indexed: 01/31/2023]
Abstract
Autophagy is a self-degradation process of cytoplasmic components and occurs in the failing heart. Angiotensin II plays a critical role in the progression of heart failure and induces autophagy. We investigated the mechanism underlying angiotensin II-enhanced autophagy and examined the role of autophagy in angiotensin II-induced cardiomyocyte injury. Neonatal rat cardiomyocytes were treated with angiotensin II (1-100 nmol/L). Angiotensin II dose-dependently increased autophagy indicators of microtubule-associated protein 1 light chain (LC) 3-II and monodansylcadaverine-labelled vesicles. It also enhanced the intracellular production of reactive oxygen species (ROS), assessed by H2DCFDA, an intracellular ROS indicator. NADPH oxidase- and mitochondria-derived ROS production was increased by angiotensin II, while angiotensin II-induced LC3-II expression was suppressed by inhibitors of these sources of ROS. Confocal microscopy revealed that superoxide-producing mitochondria colocalized with lysosomes after the angiotensin II stimulation. Myocyte apoptosis was assessed by nuclear staining with DAPI and caspase-3 activity. A 6-h stimulation with angiotensin II did not affect myocyte apoptosis, while a co-treatment with 3-methyl-adenine (3MA), an autophagy inhibitor, augmented apoptosis. These results indicate that autophagy suppressed apoptosis because it removed damaged mitochondria in the early stages of the angiotensin II stimulation. A longer angiotensin II stimulation for 24 h induced apoptosis and propidium iodide-positive lethal myocytes, while the co-treatment with 3MA did not lead to further increases. In conclusion, angiotensin II-induced autophagy removes ROS-producing mitochondria. Autophagy is a beneficial phenomenon against myocyte apoptosis in the early phase, but its benefit was limited in the late phase of angiotensin II stimulation.
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Affiliation(s)
- Miyuki Kobara
- Department of Clinical Pharmacology, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Hiroe Toba
- Department of Clinical Pharmacology, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Tetsuo Nakata
- Department of Clinical Pharmacology, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan
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Luo Y, Jiao Q, Chen Y. Targeting endoplasmic reticulum stress-the responder to lipotoxicity and modulator of non-alcoholic fatty liver diseases. Expert Opin Ther Targets 2022; 26:1073-1085. [PMID: 36657744 DOI: 10.1080/14728222.2022.2170780] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Endoplasmic reticulum (ER) stress occurs with aberrant lipid accumulation and resultant adverse effects and widely exists in nonalcoholic fatty liver disease (NAFLD). It triggers the unfolded protein response (UPR) to restore ER homeostasis and actively participates in NAFLD pathological processes, including hepatic steatosis, inflammation, hepatocyte death, and fibrosis. Such acknowledges drive the discovery of novel NAFLD biomarker and therapeutic targets and the development of ER-stress targeted NAFLD drugs. AREAS COVERED This article discusses and updates the role of ER stress and UPR in NAFLD, the underlying action mechanism, and especially their full participation in NAFLD pathophysiology. It characterizes key molecular targets useful for the prevention and treatment of NAFLD and highlights the recent ER stress-targeted therapeutic strategies for NAFLD. EXPERT OPINION Targeting ER Stress is a valuable and promising strategy for NAFLD treatment, but its smooth translation into clinical application still requires better clarification of the different UPR patterns in diverse NAFLD physiological states. Further understanding of the distinct effects of these various patterns on NAFLD, the thresholds deciding their final impacts, and their actions via non-liver tissues and cells would be of great help to develop a precise and effective therapy for NAFLD. [Figure: see text].
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Affiliation(s)
- Yu Luo
- School of Pharmaceutical Science, University of South China, Hengyang, Hunan, China
| | - Qiangqiang Jiao
- School of Pharmaceutical Science, University of South China, Hengyang, Hunan, China
| | - Yuping Chen
- School of Pharmaceutical Science, University of South China, Hengyang, Hunan, China.,Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China
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41
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Li X, Zhao Y, Gong S, Song T, Ge J, Li J, Zhang J, Fu K, Zheng Y, Ma L. Schisandrin B Ameliorates Acute Liver Injury by Regulating EGFR-mediated Activation of Autophagy. Bioorg Chem 2022; 130:106272. [DOI: 10.1016/j.bioorg.2022.106272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 10/31/2022] [Accepted: 11/10/2022] [Indexed: 11/15/2022]
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Jiao F, Zhou B, Meng L. The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases. CNS Neurosci Ther 2022; 29:37-59. [PMID: 36184826 PMCID: PMC9804079 DOI: 10.1111/cns.13985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/29/2022] [Accepted: 09/14/2022] [Indexed: 02/06/2023] Open
Abstract
The autophagy-lysosomal pathway (ALP) is involved in the degradation of protein aggregates and damaged organelles. Transcription factor EB (TFEB), a major regulator of ALP, has emerged as a leading factor in addressing neurodegenerative disease pathology, including Alzheimer's disease (AD), Parkinson's disease (PD), PolyQ diseases, and Amyotrophic lateral sclerosis (ALS). In this review, we delineate the regulation of TFEB expression and its functions in ALP. Dysfunctions of TFEB and its role in the pathogenesis of several neurodegenerative diseases are reviewed. We summarize the protective effects and molecular mechanisms of some TFEB-targeted agonists in neurodegenerative diseases. We also offer our perspective on analyzing the pros and cons of these agonists in the treatment of neurodegenerative diseases from the perspective of drug development. More studies on the regulatory mechanisms of TFEB in other biological processes will aid our understanding of the application of TFEB-targeted therapy in neurodegeneration.
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Affiliation(s)
- Fengjuan Jiao
- School of Mental HealthJining Medical UniversityJiningChina,Shandong Key Laboratory of Behavioral Medicine, School of Mental HealthJining Medical UniversityJiningChina
| | - Bojie Zhou
- School of Mental HealthJining Medical UniversityJiningChina,Shandong Key Laboratory of Behavioral Medicine, School of Mental HealthJining Medical UniversityJiningChina
| | - Lingyan Meng
- School of Mental HealthJining Medical UniversityJiningChina,Shandong Key Laboratory of Behavioral Medicine, School of Mental HealthJining Medical UniversityJiningChina
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43
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Pu J. Targeting the lysosome: Mechanisms and treatments for nonalcoholic fatty liver disease. J Cell Biochem 2022; 123:1624-1633. [PMID: 35605052 PMCID: PMC9617749 DOI: 10.1002/jcb.30274] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/24/2022] [Accepted: 05/02/2022] [Indexed: 11/11/2022]
Abstract
The multiple functions of the lysosome, including degradation, nutrient sensing, signaling, and gene regulation, enable the lysosome to regulate lipid metabolism at different levels. In this review, I summarize the recent studies on lysosomal regulation of lipid metabolism and the alterations of the lysosome functions in the livers affected by nonalcoholic fatty liver disease (NAFLD). NAFLD is a highly prevalent lipid metabolic disorder. The progression of NAFLD leads to nonalcoholic steatohepatitis (NASH) and other severe liver diseases, and thus the prevention and treatments of NAFLD progression are critically needed. Targeting the lysosome is a promising strategy. I also discuss the current manipulations of the lysosome functions in the preclinical studies of NAFLD and propose my perspectives on potential future directions.
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Affiliation(s)
- Jing Pu
- Department of Molecular Genetics and Microbiology, Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, University of New Mexico, Albuquerque, New Mexico, USA
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44
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Gao Y, Wang C, Jiang D, An G, Jin F, Zhang J, Han G, Cui C, Jiang P. New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival. Front Cell Dev Biol 2022; 10:994037. [PMID: 36187470 PMCID: PMC9524158 DOI: 10.3389/fcell.2022.994037] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/30/2022] [Indexed: 12/03/2022] Open
Abstract
Autophagy is a dynamic process that maintains the normal homeostasis of cells by digesting and degrading aging proteins and damaged organelles. The effect of autophagy on neural tissue is still a matter of debate. Some authors suggest that autophagy has a protective effect on nerve cells, whereas others suggest that autophagy also induces the death of nerve cells and aggravates nerve injury. In mammals, oxidative stress, autophagy and endoplasmic reticulum stress (ERS) constitute important defense mechanisms to help cells adapt to and survive the stress conditions caused by physiological and pathological stimuli. Under many pathophysiological conditions, oxidative stress, autophagy and ERS are integrated and amplified in cells to promote the progress of diseases. Over the past few decades, oxidative stress, autophagy and ERS and their interactions have been a hot topic in biomedical research. In this review, we summarize recent advances in understanding the interactions between oxidative stress, autophagy and ERS in neuronal cell death and survival.
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Affiliation(s)
- Yahao Gao
- Clinical Medical School, Jining Medical University, Jining, China
| | - Changshui Wang
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Di Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Gang An
- Clinical Medical School, Jining Medical University, Jining, China
| | - Feng Jin
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Junchen Zhang
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Guangkui Han
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Changmeng Cui
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
- *Correspondence: Changmeng Cui, ; Pei Jiang,
| | - Pei Jiang
- Department of Clinical Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining, China
- *Correspondence: Changmeng Cui, ; Pei Jiang,
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Invading Bacterial Pathogens Activate Transcription Factor EB in Epithelial Cells through the Amino Acid Starvation Pathway of mTORC1 Inhibition. Mol Cell Biol 2022; 42:e0024122. [PMID: 36005752 PMCID: PMC9476939 DOI: 10.1128/mcb.00241-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Upon pathogen infection, intricate innate signaling cascades are induced to initiate the transcription of immune effectors, including cytokines and chemokines. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy genes, was found recently to be a novel regulator of innate immunity in both Caenorhabditis elegans and mammals. Despite TFEB participating in critical mechanisms of pathogen recognition and in the transcriptional response to infection in mammalian macrophages, little is known about its roles in the infected epithelium or infected nonimmune cells in general. Here, we demonstrate that TFEB is activated in nonimmune cells upon infection with bacterial pathogens through a pathway dependent on mTORC1 inhibition and RAG-GTPase activity, reflecting the importance of membrane damage and amino acid starvation responses during infection. Additionally, we present data demonstrating that although TFEB does not affect bacterial killing or load in nonimmune cells, it alters the host transcriptome upon infection, thus promoting an antibacterial transcriptomic landscape. Elucidating the roles of TFEB in infected nonimmune cells and the upstream signaling cascade provides critical insight into understanding how cells recognize and respond to bacterial pathogens.
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Fu J, Wu L, Hu G, Shi Q, Wang R, Zhu L, Yu H, Fu L. AMTDB: A comprehensive database of autophagic modulators for anti-tumor drug discovery. Front Pharmacol 2022; 13:956501. [PMID: 36016573 PMCID: PMC9395961 DOI: 10.3389/fphar.2022.956501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/11/2022] [Indexed: 11/15/2022] Open
Abstract
Autophagy, originally described as a mechanism for intracellular waste disposal and recovery, has been becoming a crucial biological process closely related to many types of human tumors, including breast cancer, osteosarcoma, glioma, etc., suggesting that intervention of autophagy is a promising therapeutic strategy for cancer drug development. Therefore, a high-quality database is crucial for unraveling the complicated relationship between autophagy and human cancers, elucidating the crosstalk between the key autophagic pathways, and autophagic modulators with their remarkable antitumor activities. To achieve this goal, a comprehensive database of autophagic modulators (AMTDB) was developed. AMTDB focuses on 153 cancer types, 1,153 autophagic regulators, 860 targets, and 2,046 mechanisms/signaling pathways. In addition, a variety of classification methods, advanced retrieval, and target prediction functions are provided exclusively to cater to the different demands of users. Collectively, AMTDB is expected to serve as a powerful online resource to provide a new clue for the discovery of more candidate cancer drugs.
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Affiliation(s)
- Jiahui Fu
- School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Lifeng Wu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Gaoyong Hu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qiqi Shi
- School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Ruodi Wang
- School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
| | - Lingjuan Zhu
- School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China
- *Correspondence: Leilei Fu, ; Haiyang Yu, ; Lingjuan Zhu,
| | - Haiyang Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Leilei Fu, ; Haiyang Yu, ; Lingjuan Zhu,
| | - Leilei Fu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
- *Correspondence: Leilei Fu, ; Haiyang Yu, ; Lingjuan Zhu,
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47
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Zhang Y, Chen Y. Roles of organelle-specific autophagy in hepatocytes in the development and treatment of non-alcoholic fatty liver disease. Chin Med J (Engl) 2022; 135:1673-1681. [PMID: 35950774 PMCID: PMC9509094 DOI: 10.1097/cm9.0000000000002263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Indexed: 02/04/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disorder of lipid metabolism. The lipotoxic intermediates of lipid metabolism cause mitochondrial dysfunction and endoplasmic reticulum stress. Organelle-specific autophagy is responsible for the removal of dysfunctional organelles to maintain intracellular homeostasis. Lipophagy contributes to lipid turnover by degrading lipid droplets. The level of autophagy changes during the course of NAFLD, and the activation of hepatocyte autophagy might represent a method of treating NAFLD.
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Affiliation(s)
- Yizhi Zhang
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You’an Hospital Affiliated to Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing 100069, China
| | - Yu Chen
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You’an Hospital Affiliated to Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing 100069, China
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48
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Zhang N, Wu Y, Zhong W, Xia G, Xia H, Wang L, Wei X, Li Y, Shang H, He H, Lin S. Multiple anti-non-alcoholic steatohepatitis (NASH) efficacies of isopropylidenyl anemosapogenin via farnesoid X receptor activation and TFEB-mediated autophagy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 102:154148. [PMID: 35576742 DOI: 10.1016/j.phymed.2022.154148] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) can develop into cirrhosis, liver failure, or hepatocellular carcinoma without effective treatment. However, there are currently no drugs for NASH treatment, and the development of new therapeutics has remained a major challenge in NASH research. Advances in traditional Chinese medicine to treat liver disease inspired us to search for new NASH candidates from Chi-Shao, a widely used traditional Chinese medicine. PURPOSE In this research, we aimed to clarify the anti-NASH effect and the underlying mechanism of isopropylidenyl anemosapogenin (IA, 1), which was a new lead compound isolated from Chi-Shao. STUDY DESIGN AND METHODS Isopropylidenyl anemosapogenin (IA, 1) was first discovered by collagen type I α 1 promoter luciferase bioassay-guided isolation and then characterized by single crystal X-ray diffraction analysis and enriched by semi-synthesis. Using various molecular biology techniques, the multiple anti-NASH efficacies and mechanisms of IA were clarified based on in vitro LX-2 and Huh7 cell models, along with the in vivo choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced mouse model and bile duct ligation (BDL)-induced rat model. The UPLC-MS/MS method was used to assess the plasma concentration of IA. RESULTS A new lead compound IA was isolated from the traditional Chinese medicine Chi-Shao, which showed significant anti-liver fibrosis activity in TGF-β1-treated LX-2 cells and anti-liver steatosis activity in oleic acid-treated Huh7 cells. Furthermore, IA could significantly ameliorate in vivo CDAHFD-induced liver injury by activating the farnesoid X receptor pathway, including its targets Nr0b2, Abcb11, and Slc10a2. Simultaneously, IA activated the autophagy pathway by activating the TFEB factor, thereby promoting lipid degradation. Its liver-protective and anti-fibrosis activities were verified by the BDL-induced rat model. Finally, with an oral administration of 100 mg/kg, IA achieved the maximum plasma concentration of 1.23 ± 0.18 μg/ml at 2.67 ± 0.58 h. CONCLUSION IA, an unreported lupine-type triterpenoid isolated from Chi-shao, can significantly alleviate liver injury and fibrosis via farnesoid X receptor activation and TFEB-mediated autophagy, which indicates that IA could serve as a novel therapeutic candidate against NASH.
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Affiliation(s)
- Na Zhang
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yuzhuo Wu
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Wanchao Zhong
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Guiyang Xia
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Huan Xia
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Lingyan Wang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Xiaohong Wei
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Yi Li
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Hongwei He
- NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Sheng Lin
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China.
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Hamedi KR, Harmon KA, Goodwin RL, Arce S. Autophagy and the Bone Marrow Microenvironment: A Review of Protective Factors in the Development and Maintenance of Multiple Myeloma. Front Immunol 2022; 13:889954. [PMID: 35663979 PMCID: PMC9161817 DOI: 10.3389/fimmu.2022.889954] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/19/2022] [Indexed: 11/29/2022] Open
Abstract
The role of the unfolded protein response (UPR) in plasma cells (PC) and their malignant multiple myeloma (MM) counterparts is a well described area of research. The importance of autophagy in these cells, as well as the interplay between autophagy and the UPR system, has also been well studied. In this review, we will discuss the relationship between these two cellular responses and how they can be utilized in MM to account for the high levels of monoclonal immunoglobulin (Ig) protein synthesis that is characteristic of this disease. Interactions between MM cells and the bone marrow (BM) microenvironment and how MM cells utilize the UPR/autophagy pathway for their survival. These interacting pathways form the foundation for the mechanism of action for bortezomib, a proteasome inhibitor used to modify the progression of MM, and the eventual drug resistance that MM cells develop. One important resistance pathway implicated in MM progression is caspase 10 which attenuates autophagy to maintain its prosurvival function and avoid cell death. We lay a groundwork for future research including 3D in vitro models for better disease monitoring and personalized treatment. We also highlight pathways involved in MM cell survival and drug resistance that could be used as new targets for effective treatment.
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Affiliation(s)
- Kamron R Hamedi
- University of South Carolina School of Medicine Greenville, University of South Carolina, Greenville, SC, United States
| | - Katrina A Harmon
- Research and Development Department, Organogenesis, Birmingham, AL, United States
| | - Richard L Goodwin
- Biomedical Sciences, University of South Carolina School of Medicine Greenville, University of South Carolina, Greenville, SC, United States
| | - Sergio Arce
- Biomedical Sciences, University of South Carolina School of Medicine Greenville, University of South Carolina, Greenville, SC, United States.,Prisma Health Cancer Institute, Prisma Health System, Greenville, SC, United States
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50
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Role of TFEB in Autophagy and the Pathogenesis of Liver Diseases. Biomolecules 2022; 12:biom12050672. [PMID: 35625599 PMCID: PMC9139110 DOI: 10.3390/biom12050672] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/29/2022] [Accepted: 05/03/2022] [Indexed: 12/13/2022] Open
Abstract
The transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. Mechanistic target of rapamycin (mTOR)-mediated phosphorylation on TFEB is known to regulate TFEB subcellular localization and activity at the lysosomal surface. Recent studies have shown that TFEB also plays a critical role in physiological processes such as lipid metabolism, and dysfunction of TFEB has been observed in the pathogenesis of several diseases. Owing to its ability to improve disease status in murine models, TFEB has attracted attention as a therapeutic target for diseases. In this review, we will present the regulation of TFEB and its role in the pathogenesis of liver diseases, particularly non-alcoholic fatty liver disease (NAFLD).
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