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Wang W, Li Y, Li Y, Zhao YM, Ye JB, Qian T. Tetrandrine mediates autophagy via sirtuin 3/adenosine 5-monophosphate-activated protein kinase/mammalian target of rapamycin signal pathway to attenuate early brain injury after subarachnoid hemorrhage. Neuroreport 2025:00001756-990000000-00360. [PMID: 40377960 DOI: 10.1097/wnr.0000000000002171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
Early brain injury (EBI) is the main cause of poor outcomes in patients with subarachnoid hemorrhage (SAH). Tetrandrine (Tet) is the root of Stephania tetrandra S Moore extract that has been shown to promote neuronal survival and regulate a variety of signaling pathways; however, the mechanism through which it exerts neuroprotective effects in patients with SAH is unknown. This investigation was to examine Tet's effect on EBI in SAH rats. We divided the rats into four groups. The effects of Tet treatment on the pathological changes of neurons in rat brains were evaluated, as well as autophagy-related and signaling pathway proteins. We found that Tet had a neuroprotective effect on EBI after SAH, as evidenced by the fact that Tet ameliorated SAH-mediated neurologic impairment and neuronal morphological damage and reduced brain water content, neuronal apoptosis rate, and neuronal cell loss. Tet decreased the LC3II/LC3I ratio, elevated P62 protein expression, and inhibited autophagosome production after SAH. Tet may have increased sirtuin 3 (SIRT3) expression, decreased adenosine 5-monophosphate-activated protein kinase (AMPK) phosphorylation, and increased phosphor-mammalian target of rapamycin (mTOR) levels, all of which may have occurred particularly via SIRT3/AMPK/mTOR signaling pathway activation; However, this trend can be reversed by 3-(1H-1,2,3-triazol-4-yl) pyridine (SIRT3 inhibitors). Tet exerts neuroprotective effects by inhibiting autophagy, this may be associated with SIRT3's inhibitory effect on the AMPK/mTOR signaling pathway. This inhibition could function as a potential mechanism for the neuroprotective effects observed in patients suffering from SAH.
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Affiliation(s)
- Wenliang Wang
- Department of Neurosurgery, Characteristic Medical Center of People's Armed Police Forces, Tianjin
- Graduate School, Chengde Medical University, Chengde
| | - Yang Li
- Department of Neurosurgery, Hebei General Hospital
| | - Yuan Li
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Yan-Meng Zhao
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Jia-Bei Ye
- Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Tao Qian
- Department of Neurosurgery, Hebei General Hospital
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Saei AK, Asghari N, Jahangiri B, Cordani M, Nayeri Z, Fard NA, Djavaheri-Mergny M, Moosavi MA. Drug repositioning and experimental validation for targeting ZZ domain of p62 as a cancer treatment. Comput Biol Med 2025; 188:109757. [PMID: 39983356 DOI: 10.1016/j.compbiomed.2025.109757] [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: 09/15/2024] [Revised: 01/24/2025] [Accepted: 01/25/2025] [Indexed: 02/23/2025]
Abstract
Cancer treatment is often confounded by development of resistance to chemotherapy. This research explores the complex relationship between p62 (also known as SQSTM1), a multifunctional protein central in cancer signaling pathways - especially the NF-κB pathway - and chemoresistance. Our data indicate that disruption of the interaction between p62 and the serine/threonine protein kinase RIP1 is a viable strategy to counteract NF-κB activation and overcome chemoresistance. Employing a comprehensive drug repositioning approach, we utilized bioinformatics tools to perform docking, virtual screening, absorption, distribution, metabolism, and excretion analyses, toxicity analysis, and molecular dynamics simulations to identify FDA-approved drugs that prevent the binding of p62 to RIP1. Notable candidates, particularly montelukast and asunaprevir, blocked the p62-RIP1 interaction, establishing a basis for potential therapeutic interventions against chemoresistant cancers. This study highlights the critical role of the ZZ domain of p62 protein in chemotherapy resistance and sheds light on the possibility of repurposing existing drugs for novel applications in cancer treatment. Our findings provide a solid groundwork for preclinical studies.
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Affiliation(s)
- Ali Kian Saei
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran
| | - Narjes Asghari
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran
| | - Babak Jahangiri
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain
| | - Zahra Nayeri
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran
| | - Najaf Allahyari Fard
- Department of Systems Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Mojgan Djavaheri-Mergny
- Team «Metabolism, Cancer & Immunity », Centre de Recherche des Cordeliers, INSERM UMRS1138, Sorbonne Université, Université de Paris, 75006, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, 94800 France
| | - Mohammad Amin Moosavi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran.
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Yang X, Cao X, Zhu Q. p62/SQSTM1 in cancer: phenomena, mechanisms, and regulation in DNA damage repair. Cancer Metastasis Rev 2025; 44:33. [PMID: 39954143 PMCID: PMC11829845 DOI: 10.1007/s10555-025-10250-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/06/2025] [Indexed: 02/17/2025]
Abstract
The multidomain protein cargo adaptor p62, also known as sequestosome 1, serves as a shuttling factor and adaptor for the degradation of substrates via the proteasome and autophagy pathways. Regarding its structure, p62 is composed of several functional domains, including the N-terminal Phox1 and Bem1p domains, a ZZ-type zinc finger domain, a LIM protein-binding domain that contains the tumor necrosis factor receptor-associated factor 6 (TRAF6) binding region, two nuclear localization signals (NLS 1/2), a nuclear export signal (NES), the LC3-interacting region (LIR), a Kelch-like ECH-associated protein 1 (KEAP1)-interacting region, and a ubiquitin-associated (UBA) domain. Recent studies have highlighted the critical role of p62 in the development and progression of various malignancies. Overexpression and/or impaired degradation of p62 are linked to the initiation and progression of numerous cancers. While p62 is primarily localized in the cytosol and often considered a cytoplasmic protein, most of the existing literature focuses on its cytoplasmic functions, leaving its nuclear roles less explored. However, an increasing body of research has uncovered p62's involvement in the cellular response to DNA damage. In this review, we summarize the current understanding of p62's molecular functions in malignancies, with particular emphasis on its role in DNA damage repair, highlighting the latest advances in this field.
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Affiliation(s)
- Xiaojuan Yang
- Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xunjie Cao
- Division of Abdominal Tumor Multimodality Treatment, Department of General Surgery, West China Hospital, Sichuan University, Cancer Center, Chengdu, 610041, China
| | - Qing Zhu
- Division of Abdominal Tumor Multimodality Treatment, Department of General Surgery, West China Hospital, Sichuan University, Cancer Center, Chengdu, 610041, China.
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Zeng X, Lafferty TK, Sehrawat A, Chen Y, Ferreira PCL, Bellaver B, Povala G, Kamboh MI, Klunk WE, Cohen AD, Lopez OL, Ikonomovic MD, Pascoal TA, Ganguli M, Villemagne VL, Snitz BE, Karikari TK. Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease. Mol Neurodegener 2024; 19:68. [PMID: 39385222 PMCID: PMC11465638 DOI: 10.1186/s13024-024-00753-5] [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: 04/23/2024] [Accepted: 09/04/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Blood-based biomarkers are gaining grounds for the detection of Alzheimer's disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced. Referred to as the NULISAseq CNS disease panel, the assay simultaneously measures ~ 120 analytes related to neurodegenerative diseases, including those linked to both core (i.e., tau and amyloid-beta (Aβ)) and non-core AD processes. This study aimed to evaluate the technical and clinical performance of this novel targeted proteomic panel. METHODS The NULISAseq CNS disease panel was applied to 176 plasma samples from 113 individuals in the MYHAT-NI cohort of predominantly cognitively normal participants from an economically underserved region in southwestern Pennsylvania, USA. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were independently measured using Single Molecule Array (Simoa) and correlations and diagnostic performances compared. Aβ pathology, tau pathology, and neurodegeneration (AT(N) statuses) were evaluated with [11C] PiB PET, [18F]AV-1451 PET, and an MRI-based AD-signature composite cortical thickness index, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA and neuroimaging-determined AT(N) biomarkers. RESULTS NULISA concurrently measured 116 plasma biomarkers with good technical performance (97.2 ± 13.9% targets gave signals above assay limits of detection), and significant correlation with Simoa assays for the classical biomarkers. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aβ-PET + participants, including TIMP3, BDNF, MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET + participants. Novel plasma biomarkers with tau PET-dependent longitudinal changes included proteins associated with neuroinflammation, synaptic function, and cerebrovascular integrity, such as CHIT1, CHI3L1, NPTX1, PGF, PDGFRB, and VEGFA; all previously linked to AD but only reliable when measured in cerebrospinal fluid. The autophagosome cargo protein SQSTM1 exhibited significant association with neurodegeneration after adjusting age, sex, and APOE ε4 genotype. CONCLUSIONS Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes, consistent with the recently revised biological and diagnostic framework. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD.
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Affiliation(s)
- Xuemei Zeng
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Tara K Lafferty
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Anuradha Sehrawat
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Yijun Chen
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Pamela C L Ferreira
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Bruna Bellaver
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Guilherme Povala
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - M Ilyas Kamboh
- Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - William E Klunk
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Ann D Cohen
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Oscar L Lopez
- Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Milos D Ikonomovic
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
- Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Geriatric Research Education and Clinical Center, VA Pittsburgh HS, Pittsburgh, PA, USA
| | - Tharick A Pascoal
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Mary Ganguli
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
- Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Victor L Villemagne
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA
| | - Beth E Snitz
- Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Thomas K Karikari
- Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA.
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Yehia A, Abulseoud OA. Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration. Mol Neurodegener 2024; 19:36. [PMID: 38641847 PMCID: PMC11031980 DOI: 10.1186/s13024-024-00728-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024] Open
Abstract
The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.
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Affiliation(s)
- Asmaa Yehia
- Department of Neuroscience, Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine, Phoenix, AZ, 58054, USA
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Osama A Abulseoud
- Department of Neuroscience, Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine, Phoenix, AZ, 58054, USA.
- Department of Psychiatry and Psychology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA.
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6
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Potes Y, Bermejo-Millo JC, Mendes C, Castelão-Baptista JP, Díaz-Luis A, Pérez-Martínez Z, Solano JJ, Sardão VA, Oliveira PJ, Caballero B, Coto-Montes A, Vega-Naredo I. p66Shc signaling and autophagy impact on C2C12 myoblast differentiation during senescence. Cell Death Dis 2024; 15:200. [PMID: 38459002 PMCID: PMC10923948 DOI: 10.1038/s41419-024-06582-0] [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: 08/02/2022] [Revised: 02/23/2024] [Accepted: 03/01/2024] [Indexed: 03/10/2024]
Abstract
During aging, muscle regenerative capacities decline, which is concomitant with the loss of satellite cells that enter in a state of irreversible senescence. However, what mechanisms are involved in myogenic senescence and differentiation are largely unknown. Here, we showed that early-passage or "young" C2C12 myoblasts activated the redox-sensitive p66Shc signaling pathway, exhibited a strong antioxidant protection and a bioenergetic profile relying predominantly on OXPHOS, responses that decrease progressively during differentiation. Furthermore, autophagy was increased in myotubes. Otherwise, late-passage or "senescent" myoblasts led to a highly metabolic profile, relying on both OXPHOS and glycolysis, that may be influenced by the loss of SQSTM1/p62 which tightly regulates the metabolic shift from aerobic glycolysis to OXPHOS. Furthermore, during differentiation of late-passage C2C12 cells, both p66Shc signaling and autophagy were impaired and this coincides with reduced myogenic capacity. Our findings recognized that the lack of p66Shc compromises the proliferation and the onset of the differentiation of C2C12 myoblasts. Moreover, the Atg7 silencing favored myoblasts growth, whereas interfered in the viability of differentiated myotubes. Then, our work demonstrates that the p66Shc signaling pathway, which highly influences cellular metabolic status and oxidative environment, is critical for the myogenic commitment and differentiation of C2C12 cells. Our findings also support that autophagy is essential for the metabolic switch observed during the differentiation of C2C12 myoblasts, confirming how its regulation determines cell fate. The regulatory roles of p66Shc and autophagy mechanisms on myogenesis require future attention as possible tools that could predict and measure the aging-related state of frailty and disability.
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Affiliation(s)
- Yaiza Potes
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain.
| | - Juan C Bermejo-Millo
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain
| | - Catarina Mendes
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - José P Castelão-Baptista
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- PDBEB - Doctoral Program in Experimental Biology and Biomedicine, Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Andrea Díaz-Luis
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
| | - Zulema Pérez-Martínez
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Microbiology service, University Central Hospital of Asturias, Oviedo, Spain
| | - Juan J Solano
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Geriatric Service, Monte Naranco Hospital, Av. Doctores Fernández Vega, Oviedo, Spain
| | - Vilma A Sardão
- CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
- MIA-Portugal - Multidisciplinary Institute of Ageing, University of Coimbra, Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- CIBB, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Beatriz Caballero
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain
| | - Ana Coto-Montes
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain
| | - Ignacio Vega-Naredo
- Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
- Institute of Neurosciences of the Principality of Asturias (INEUROPA), Oviedo, Spain.
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Shuey A, Patricelli C, Oxford JT, Pu X. Effects of doxorubicin on autophagy in fibroblasts. Hum Exp Toxicol 2024; 43:9603271241231947. [PMID: 38324556 PMCID: PMC11648171 DOI: 10.1177/09603271241231947] [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] [Indexed: 02/09/2024]
Abstract
Objectives: Doxorubicin (DOX) is a highly effective chemotherapeutic used to treat many adult and pediatric cancers, such as solid tumors, leukemia, lymphomas and breast cancer. It can also cause injuries to multiple organs, including the heart, liver, and brain or kidney, although cardiotoxicity is the most prominent side effect of DOX. In this study, we examined the potential effects of DOX on autophagy activity in two different mouse fibroblasts.Methods: Mouse embryonic fibroblasts (NIH3T3) and mouse primary cardiac fibroblasts (CFs) were treated with DOX to assess changes in the expression of two commonly used autophagy protein markers, LC3II and p62. We also examined the effects of DOX the on expression of key genes that encode components of the molecular machinery and regulators modulating autophagy in response to both extracellular and intracellular signals.Results: We observed that LC3II levels increased and p62 levels decreased following the DOX treatment in NIH3T3 cells. However, similar effects were not observed in primary cardiac fibroblasts. In addition, DOX treatment induced the upregulation of a significant number of genes involved in autophagy in NIH3T3 cells, but not in primary cardiac fibroblasts.Conclusions: Taken together, these results indicate that DOX upregulates autophagy in fibroblasts in a cell-specific manner.
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Affiliation(s)
- Anna Shuey
- Biomolecular Sciences Graduate Programs, Boise State University, Boise, ID, USA
| | - Conner Patricelli
- Biomolecular Sciences Graduate Programs, Boise State University, Boise, ID, USA
| | - Julia T Oxford
- Biomolecular Sciences Graduate Programs, Boise State University, Boise, ID, USA
- Biomolecular Research Center, Boise State University, Boise, ID, USA
- Department of Biological Sciences, Boise State University, Boise, ID, USA
| | - Xinzhu Pu
- Biomolecular Research Center, Boise State University, Boise, ID, USA
- Department of Biological Sciences, Boise State University, Boise, ID, USA
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8
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Currais A, Raschke W, Maher P. CMS121, a Novel Drug Candidate for the Treatment of Alzheimer's Disease and Age-Related Dementia. J Alzheimers Dis 2024; 101:S179-S192. [PMID: 39422940 DOI: 10.3233/jad-231062] [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] [Indexed: 10/19/2024]
Abstract
Old age is the major risk factor for sporadic Alzheimer's disease (AD). However, old age-related changes in brain physiology have generally not been taken into consideration in developing drug candidates for the treatment of AD. This is at least partly because the role of these age-related processes in the development and progression of AD are still not well understood. Nevertheless, we and others have described an association between the oxytosis/ferroptosis non-apoptotic regulated cell death pathway and aging. Based on this association, we incorporated protection against this pathway as part of a cell-based phenotypic screening approach to identify novel drug candidates for the treatment of AD. Using this approach, we identified the fisetin derivative CMS121 as a potent neuroprotective molecule that is able to maintain cognitive function in multiple pre-clinical models of AD. Furthermore, we identified a key target of CMS121 as fatty acid synthase, a protein which had not been previously considered in the context of AD. Herein, we provide a comprehensive description of the development of CMS121, its preclinical activities, and the results of the toxicology testing that led to its IND approval.
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Affiliation(s)
| | | | - Pamela Maher
- Salk Institute for Biological Studies, La Jolla, CA, USA
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9
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Chowdhury SG, Karmakar P. Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach. Mol Biol Rep 2023; 51:3. [PMID: 38063905 DOI: 10.1007/s11033-023-08961-w] [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: 08/17/2023] [Accepted: 10/26/2023] [Indexed: 12/18/2023]
Abstract
Autophagy is a process that is characterized by the destruction of redundant components and the removal of dysfunctional ones to maintain cellular homeostasis. Autophagy dysregulation has been linked to various illnesses, such as neurodegenerative disorders and cancer. The precise transcription of the genes involved in autophagy is regulated by a network of epigenetic factors. This includes histone modifications and histone-modifying enzymes. Epigenetics is a broad category of heritable, reversible changes in gene expression that do not include changes to DNA sequences, such as chromatin remodeling, histone modifications, and DNA methylation. In addition to affecting the genes that are involved in autophagy, the epigenetic machinery can also alter the signals that control this process. In cancer, autophagy plays a dual role by preventing the development of tumors on one hand and this process may suppress tumor progression. This may be the control of an oncogene that prevents autophagy while, conversely, tumor suppression may promote it. The development of new therapeutic strategies for autophagy-related disorders could be initiated by gaining a deeper understanding of its intricate regulatory framework. There is evidence showing that certain machineries and regulators of autophagy are affected by post-translational and epigenetic modifications, which can lead to alterations in the levels of autophagy and these changes can then trigger disease or affect the therapeutic efficacy of drugs. The goal of this review is to identify the regulatory pathways associated with post-translational and epigenetic modifications of different proteins in autophagy which may be the therapeutic targets shortly.
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Affiliation(s)
| | - Parimal Karmakar
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, 700032, India.
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10
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Xu L, Zhang H, Yuan H, Xie L, Zhang J, Liang Z. Not your usual neurodegenerative disease: a case report of neuronal intranuclear inclusion disease with unconventional imaging patterns. Front Neurosci 2023; 17:1247403. [PMID: 37638306 PMCID: PMC10447982 DOI: 10.3389/fnins.2023.1247403] [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: 06/26/2023] [Accepted: 07/31/2023] [Indexed: 08/29/2023] Open
Abstract
Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative illness with characteristic brain magnetic resonance imaging (MRI) manifestations: diffuse symmetric white-matter hyperintensities in lateral cerebral ventricle areas in fluid-attenuated inversion recovery (FLAIR) and high-intensity signals along the corticomedullary junction of the frontal-parietal-temporal lobes in diffusion weighted imaging (DWI). Here, we report a case of adult-onset NIID who was misdiagnosed with Susac syndrome (SS) due to unusual corpus callosum imaging findings. Case presentation A 39-year-old man presented with chronic headache, blurred vision, tinnitus, and numbness in the hands as initial symptoms, accompanied by cognitive slowing and decreased memory. Brain MRI revealed round hypointense lesions on T1-weighted imaging (T1WI) and hyperintense lesions on T2WI/FLAIR/DWI in the genu and splenium of the corpus callosum. An initial diagnosis of SS was made based on the presence of the SS-typical symptoms and SS-characteristic radiology changes. Furthermore, the patient's symptoms improved upon completion of a combined pharmacotherapy plan. However, no significant changes were evident 18 months after the brain MRI scan. Eventually, the patient was then diagnosed with NIID based on a skin biopsy and detection of expanded GGC (guanine, guanine, cytosine) repeats in the NOTCH2NLC gene. Conclusion The present NIID case in which there was simultaneous onset of altered nervous and visual system functioning and atypical imaging findings, the atypical imaging findings may reflect an initial change of NIID leukoencephalopathy.
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Affiliation(s)
| | | | | | | | | | - Zhigang Liang
- Department of Neurology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, China
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11
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Alkashash A, Samiei A, Alomari AK. The new and old in superficial mesenchymal tumors with uncertain origin and/or melanocytic differentiation. Semin Diagn Pathol 2023; 40:258-266. [PMID: 37120349 DOI: 10.1053/j.semdp.2023.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 04/24/2023] [Indexed: 05/01/2023]
Affiliation(s)
- Ahmad Alkashash
- Department of Pathology and Laboratory Medicine, Indiana University, School of Medicine, Indianapolis, IN, United States
| | - Azadeh Samiei
- Department of Pathology and Laboratory Medicine, Indiana University, School of Medicine, Indianapolis, IN, United States
| | - Ahmed K Alomari
- Department of Pathology and Laboratory Medicine, Indiana University, School of Medicine, Indianapolis, IN, United States.
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12
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Zhang X, Dai M, Li S, Li M, Cheng B, Ma T, Zhou Z. The emerging potential role of p62 in cancer treatment by regulating metabolism. Trends Endocrinol Metab 2023:S1043-2760(23)00106-6. [PMID: 37349161 DOI: 10.1016/j.tem.2023.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/17/2023] [Accepted: 05/22/2023] [Indexed: 06/24/2023]
Abstract
p62 is an important multifunctional adaptor protein participating in autophagy and many other activities. Many studies have revealed that p62 is highly expressed in multiple cancers and decreasing its level can effectively lower the proliferation ability of cancer cells. Moreover, much research has highlighted the significant role of the regulation of cancer cell metabolism in helping to treat tumors. Recent reports demonstrate that p62 could regulate cancer cell metabolism through various mechanisms. However, the relationship between p62 and cancer cell metabolism as well as the related mechanisms has not been fully elucidated. In this review, we describe glucose, glutamine, and fatty acid metabolism in tumor cells and some signaling pathways that can regulate cancer metabolism and are mediated by p62.
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Affiliation(s)
- Xiaochuan Zhang
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China
| | - Mengge Dai
- School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Shaotong Li
- School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Meng Li
- School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Bing Cheng
- School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Ting Ma
- School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
| | - Zheng Zhou
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China.
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13
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Zaki ES, Sayed RH, Saad MA, El-Yamany MF. Roflumilast ameliorates ovariectomy-induced depressive-like behavior in rats via activation of AMPK/mTOR/ULK1-dependent autophagy pathway. Life Sci 2023:121806. [PMID: 37257579 DOI: 10.1016/j.lfs.2023.121806] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/14/2023] [Accepted: 05/23/2023] [Indexed: 06/02/2023]
Abstract
AIMS Roflumilast, a well-known phosphodiesterase-4 (PDE-4) inhibitor, possess an anti-inflammatory activity with approved indications in chronic obstructive pulmonary disease. This study aimed to evaluate the neuroprotective role of roflumilast in ovariectomy (OVX)-induced depressive-like behavior in female rats and to shed light on a potential autophagy enhancing effect. MAIN METHODS Rats were randomly divided into four groups: sham, OVX, OVX + roflumilast (1 mg/kg, p.o), and OVX + roflumilast + chloroquine (CQ) (50 mg/kg, i.p). Drugs were administered for 4 weeks starting 2 weeks after OVX. KEY FINDINGS Roflumilast improved the depressive-like behaviors observed in OVX rats as evidenced by decreasing both forced swimming and open field immobility times while, increasing % sucrose preference and number of open field crossed squares. Histopathological analysis provides further evidence of roflumilast's beneficial effects, demonstrating that roflumilast ameliorated the neuronal damage caused by OVX. Roflumilast antidepressant potential was mediated via restoring hippocampal cAMP and BDNF levels as well as down-regulating PDE4 expression. Moreover, roflumilast revealed anti-inflammatory and anti-apoptotic effects via hindering TNF-α level and diminishing Bax/Bcl2 ratio. Roflumilast restored the autophagic function via up-regulation of p-AMPK, p-ULK1, Beclin-1 and LC3II/I expression, along with downregulation of P62 level and p-mTOR protein expression. The autophagy inhibitor CQ was used to demonstrate the suggested pathway. SIGNIFICANCE The present study revealed that roflumilast showed an anti-depressant activity in OVX female rats via turning on AMPK/mTOR/ULK1-dependent autophagy pathway; and neurotrophic, anti-inflammatory, and anti-apoptotic activities. Roflumilast could offer a more secure alternative to hormone replacement therapy for postmenopausal depression treatment.
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Affiliation(s)
- Eman S Zaki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Rabab H Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Muhammed A Saad
- Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman, 4184, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Muhammed F El-Yamany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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14
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Trigo D, Nadais A, Carvalho A, Morgado B, Santos F, Nóbrega-Pereira S, da Cruz E Silva OAB. Mitochondria dysfunction and impaired response to oxidative stress promotes proteostasis disruption in aged human cells. Mitochondrion 2023; 69:1-9. [PMID: 36273801 DOI: 10.1016/j.mito.2022.10.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 08/19/2022] [Accepted: 10/15/2022] [Indexed: 12/06/2022]
Abstract
The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles ensuring that varying energetic demands are rapidly met. Given the brain's high energy demand, mitochondria play a particularly critical role in neuronal and axonal energy homeostasis. With ageing physiological properties of the organism deteriorate, and are associated with loss of cellular homeostasis, accumulation of dysfunctional organelles and damaged macromolecules. Thus, mitochondrial loss of efficiency is likely to be both a cause and a consequence of ageing. Additionally distinct cellular events can contribute to oxidative stress, disruption of metabolism and mitochondria homeostasis, resulting in neuropathology. However, although the correlation between ageing and mitochondria disfunction is well established, the response to oxidative stress, particularly proteostasis, remains to be fully elucidated. The work here described explores the degradation of mitochondria oxidative stress-response mechanisms with ageing in human cells, addressing the physiological effects on proteostasis, focused on its role in differentiating between healthy and pathological ageing. Increased protein aggregation appears to be tightly related to impairment of ageing mitochondria response to oxidative stress, and antioxidative agents are shown to have a progressive protective effect with age; cells from old individuals show higher susceptibility to oxidative stress, in terms of protein aggregation, cell viability, or mitochondria homeostasis. These results support the antioxidant properties of flavonoids as a good therapeutic strategy for age-related diseases. Given their protective effect, this family of compounds can be of strategic therapeutic value for protein-aggregation related diseases.
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Affiliation(s)
- Diogo Trigo
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal.
| | - André Nadais
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ana Carvalho
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bárbara Morgado
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Francisco Santos
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Sandrina Nóbrega-Pereira
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Odete A B da Cruz E Silva
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
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15
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Qian H, Chao X, Wang S, Li Y, Jiang X, Sun Z, Rülicke T, Zatloukal K, Ni HM, Ding WX. Loss of SQSTM1/p62 Induces Obesity and Exacerbates Alcohol-Induced Liver Injury in Aged Mice. Cell Mol Gastroenterol Hepatol 2023; 15:1027-1049. [PMID: 36754207 PMCID: PMC10036741 DOI: 10.1016/j.jcmgh.2023.01.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/10/2023]
Abstract
BACKGROUND Alcohol-associated liver disease (ALD) is a worldwide health problem, of which the effective treatment is still lacking. Both detrimental and protective roles of adipose tissue have been implicated in ALD. Although alcohol increases adipose tissue lipolysis to promote alcohol-induced liver injury, alcohol also activates brown adipose tissue (BAT) thermogenesis as an adaptive response in protecting against alcohol-induced liver injury. Moreover, aging and obesity are also risk factors for ALD. In the present study, we investigated the effects of autophagy receptor protein SQSTM1/p62 on adipose tissue and obesity in alcohol-induced liver injury in both young and aged mice. METHODS Young and aged whole-body SQSTM1/p62 knockout (KO) and their age-matched wild-type (WT) mice were subjected to chronic plus binge (Gao-binge) alcohol feeding. Blood, adipose and liver tissues were collected for biochemical and histologic analysis. RESULTS Aged but not young SQSTM1/p62 KO mice had significantly increased body weight and fat mass compared with the matched WT mice. Gao-binge alcohol feeding induced white adipose atrophy and decreased levels of SQSTM1/p62 levels in adipose tissue in aged WT mice. SQSTM1/p62 KO aged mice were resistant to Gao-binge alcohol-induced white adipose atrophy. Alcohol feeding increased the expression of thermogenic genes in WT mouse BAT, which was significantly blunted in SQSTM1/p62 KO aged mice. Alcohol-fed aged SQSTM1/p62 KO mice showed significantly higher levels of serum alanine aminotransferase, hepatic triglyceride, and inflammation compared with young and aged WT mice fed with alcohol. Alcohol-fed SQSTM1/p62 KO mice also increased secretion of proinflammatory and angiogenic adipokines that may promote alcohol-induced liver injury. CONCLUSIONS Loss of SQSTM1/p62 in aged mice leads to obesity and impairs alcohol-induced BAT adaptation, resulting in exacerbated alcohol-induced liver injury in mice.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Yuan Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Xiaoxiao Jiang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Thomas Rülicke
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Kurt Zatloukal
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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16
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Möller S, Saul N, Projahn E, Barrantes I, Gézsi A, Walter M, Antal P, Fuellen G. Gene co-expression analyses of health(span) across multiple species. NAR Genom Bioinform 2022; 4:lqac083. [PMID: 36458022 PMCID: PMC9706456 DOI: 10.1093/nargab/lqac083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 08/20/2022] [Accepted: 10/31/2022] [Indexed: 12/03/2022] Open
Abstract
Health(span)-related gene clusters/modules were recently identified based on knowledge about the cross-species genetic basis of health, to interpret transcriptomic datasets describing health-related interventions. However, the cross-species comparison of health-related observations reveals a lot of heterogeneity, not least due to widely varying health(span) definitions and study designs, posing a challenge for the exploration of conserved healthspan modules and, specifically, their transfer across species. To improve the identification and exploration of conserved/transferable healthspan modules, here we apply an established workflow based on gene co-expression network analyses employing GEO/ArrayExpress data for human and animal models, and perform a comprehensive meta-study of the resulting modules related to health(span), yielding a small set of literature backed health(span) candidate genes. For each experiment, WGCNA (weighted gene correlation network analysis) was used to infer modules of genes which correlate in their expression with a 'health phenotype score' and to determine the most-connected (hub) genes (and their interactions) for each such module. After mapping these hub genes to their human orthologs, 12 health(span) genes were identified in at least two species (ACTN3, ANK1, MRPL18, MYL1, PAXIP1, PPP1CA, SCN3B, SDCBP, SKIV2L, TUBG1, TYROBP, WIPF1), for which enrichment analysis by g:profiler found an association with actin filament-based movement and associated organelles, as well as muscular structures. We conclude that a meta-study of hub genes from co-expression network analyses for the complex phenotype health(span), across multiple species, can yield molecular-mechanistic insights and can direct experimentalists to further investigate the contribution of individual genes and their interactions to health(span).
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Affiliation(s)
- Steffen Möller
- To whom correspondence should be addressed. Tel: +49 381 494 7361; Fax: +49 381 494 7203;
| | - Nadine Saul
- Humboldt-University of Berlin, Institute of Biology, Berlin, Germany
| | - Elias Projahn
- Rostock University Medical Center, Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock, Germany
| | - Israel Barrantes
- Rostock University Medical Center, Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock, Germany
| | - András Gézsi
- Budapest University of Technology and Economics, Department of Measurement and Information Systems, Budapest, Hungary
| | - Michael Walter
- Rostock University Medical Center, Institute for Clinical Chemistry and Laboratory Medicine, Rostock, Germany
| | - Péter Antal
- Budapest University of Technology and Economics, Department of Measurement and Information Systems, Budapest, Hungary
| | - Georg Fuellen
- Rostock University Medical Center, Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock, Germany
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17
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Rubin de Celis MF, Garcia-Martin R, Syed I, Lee J, Aguayo-Mazzucato C, Bonner-Weir S, Kahn BB. PAHSAs reduce cellular senescence and protect pancreatic beta cells from metabolic stress through regulation of Mdm2/p53. Proc Natl Acad Sci U S A 2022; 119:e2206923119. [PMID: 36375063 PMCID: PMC9704710 DOI: 10.1073/pnas.2206923119] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022] Open
Abstract
Senescence in pancreatic beta cells plays a major role in beta cell dysfunction, which leads to impaired glucose homeostasis and diabetes. Therefore, prevention of beta cell senescence could reduce the risk of diabetes. Treatment of nonobese diabetic (NOD) mice, a model of type 1 autoimmune diabetes (T1D), with palmitic acid hydroxy stearic acids (PAHSAs), a novel class of endogenous lipids with antidiabetic and antiinflammatory effects, delays the onset and reduces the incidence of T1D from 82% with vehicle treatment to 35% with PAHSAs. Here, we show that a major mechanism by which PAHSAs protect islets of the NOD mice is by directly preventing and reversing the initial steps of metabolic stress-induced senescence. In vitro PAHSAs increased Mdm2 expression, which decreases the stability of p53, a key inducer of senescence-related genes. In addition, PAHSAs enhanced expression of protective genes, such as those regulating DNA repair and glutathione metabolism and promoting autophagy. We demonstrate the translational relevance by showing that PAHSAs prevent and reverse early stages of senescence in metabolically stressed human islets by the same Mdm2 mechanism. Thus, a major mechanism for the dramatic effect of PAHSAs in reducing the incidence of type 1 diabetes in NOD mice is decreasing cellular senescence; PAHSAs may have a similar benefit in humans.
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Affiliation(s)
- Maria F. Rubin de Celis
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
| | | | - Ismail Syed
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
| | - Jennifer Lee
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
| | | | | | - Barbara B. Kahn
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
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18
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Trelford CB, Dagnino L, Di Guglielmo GM. Transforming growth factor-β in tumour development. Front Mol Biosci 2022; 9:991612. [PMID: 36267157 PMCID: PMC9577372 DOI: 10.3389/fmolb.2022.991612] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 09/15/2022] [Indexed: 11/14/2022] Open
Abstract
Transforming growth factor-β (TGFβ) is a ubiquitous cytokine essential for embryonic development and postnatal tissue homeostasis. TGFβ signalling regulates several biological processes including cell growth, proliferation, apoptosis, immune function, and tissue repair following injury. Aberrant TGFβ signalling has been implicated in tumour progression and metastasis. Tumour cells, in conjunction with their microenvironment, may augment tumourigenesis using TGFβ to induce epithelial-mesenchymal transition, angiogenesis, lymphangiogenesis, immune suppression, and autophagy. Therapies that target TGFβ synthesis, TGFβ-TGFβ receptor complexes or TGFβ receptor kinase activity have proven successful in tissue culture and in animal models, yet, due to limited understanding of TGFβ biology, the outcomes of clinical trials are poor. Here, we review TGFβ signalling pathways, the biology of TGFβ during tumourigenesis, and how protein quality control pathways contribute to the tumour-promoting outcomes of TGFβ signalling.
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Affiliation(s)
- Charles B. Trelford
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Lina Dagnino
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Department of Oncology, Children’s Health Research Institute and Lawson Health Research Institute, London, ON, Canada
| | - Gianni M. Di Guglielmo
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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Pan S, Guo S, Dai J, Gu Y, Wang G, Wang Y, Qin Z, Luo L. Trehalose ameliorates autophagy dysregulation in aged cortex and acts as an exercise mimetic to delay brain aging in elderly mice. FOOD SCIENCE AND HUMAN WELLNESS 2022. [DOI: 10.1016/j.fshw.2022.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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20
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Wang L, Hensley CR, Howell ME, Ning S. Bioinformatics-Driven Identification of p62 as A Crucial Oncogene in Liver Cancer. Front Oncol 2022; 12:923009. [PMID: 35814476 PMCID: PMC9263135 DOI: 10.3389/fonc.2022.923009] [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: 04/18/2022] [Accepted: 05/27/2022] [Indexed: 11/26/2022] Open
Abstract
Liver hepatocellular carcinoma (LIHC) is the major form of liver cancer that is the fourth most common cause of cancer death worldwide. It has been reported that the multifunctional protein p62 (also known as SQSTM1) plays a cancer-promoting role in LIHC, but the detailed mechanisms underlying p62 interaction with LIHC remains unclear. To gain a comprehensive understanding of p62 interaction with LIHC in clinical settings, we performed bioinformatic analyses using various online algorithms derived from high throughput profiling. Our results indicate that p62 expression is significantly upregulated, partially due to its promoter demethylation, rather than p62 gene mutation, in LIHC. Mutation of TP53, CTNNB1, or ALB significantly correlates with, and mutation of AXIN1 reversely correlates with, the p62 expression level. Its upregulation occurs as early as liver cirrhosis, and go through all stages of the carcinogenesis. HCV infection makes a significant contribution to p62 upregulation in LIHC. We further identified p62-associated molecular signatures in LIHC, including many genes that are involved in antioxidant stress and metabolism, such as SRX1 and TXNRD1. Regarding to the clinical outcome, p62 expression level reversely correlates with the survival of LIHC patients (p<0.01). Importantly, we experimentally validated that p62 depletion in liver cancer cell lines downregulates the expression of SRX1 and TXNRD1 at both transcriptional and translational levels, and reduces cell proliferation. As the potential mechanisms underlying the tumor-promoting role of p62, we show that p62 upregulation is remarkably associated with reprogramming of pathways mediated by p53, Wnt/β-catenin, and Keap1-NRF2, which are crucial for oncogenesis in many contexts. Our findings provide a comprehensive insight into the interaction between p62 and LIHC, offering valuable information for understanding of LIHC pathogenesis.
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Affiliation(s)
- Ling Wang
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- *Correspondence: Ling Wang,
| | - Culton R. Hensley
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Mary E. Howell
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Shunbin Ning
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
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21
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Zhang Y, Liu S, Xu Q, Li H, Lu K. Cleavage of the selective autophagy receptor SQSTM1/p62 by the SARS-CoV-2 main protease NSP5 prevents the autophagic degradation of viral membrane proteins. MOLECULAR BIOMEDICINE 2022; 3:17. [PMID: 35654983 PMCID: PMC9162485 DOI: 10.1186/s43556-022-00083-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/16/2022] [Indexed: 02/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) global pandemic. Omicron, a new variant of SARS-CoV-2, has the characteristics of strong transmission and pathogenicity, short incubation period, and rapid onset progression, and has spread rapidly around the world. The high replication rate and intracellular accumulation of SARS-CoV-2 are remarkable, but the underlying molecular mechanisms remain unclear. Autophagy acts as a conservative cellular defence mechanism against invading pathogens. Here, we provide evidence that the main protease of SARS-CoV-2, NSP5, effectively cleaves the selective autophagy receptor p62. NSP5 targets p62 for cleavage at glutamic acid 354 and thus abolishes the capacity of p62 to mediate selective autophagy. It was further shown that p62 specifically interacted with ubiquitinated SARS-CoV-2 M, the viral membrane protein, to promote its autophagic degradation. In the presence of NSP5, p62-mediated autophagic degradation of the M protein was inhibited. The cleaved products of p62 also cannot facilitate the degradation of the M protein. Collectively, our findings reveal that p62 is a novel host target of SARS-CoV-2 NSP5 and suggest that selective autophagy targets viruses and potential strategies by which the virus evades autophagic clearance. Our results may provide new ideas for the development of anti-COVID-19 drugs based on autophagy and NSP5.
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Affiliation(s)
- Yabin Zhang
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Shiyan Liu
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qingjia Xu
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Huihui Li
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Kefeng Lu
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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22
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Kumar AV, Mills J, Lapierre LR. Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging. Front Cell Dev Biol 2022; 10:793328. [PMID: 35237597 PMCID: PMC8883344 DOI: 10.3389/fcell.2022.793328] [Citation(s) in RCA: 160] [Impact Index Per Article: 53.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/19/2022] [Indexed: 12/29/2022] Open
Abstract
Efficient proteostasis is crucial for somatic maintenance, and its decline during aging leads to cellular dysfunction and disease. Selective autophagy is a form of autophagy mediated by receptors that target specific cargoes for degradation and is an essential process to maintain proteostasis. The protein Sequestosome 1 (p62/SQSTM1) is a classical selective autophagy receptor, but it also has roles in the ubiquitin-proteasome system, cellular metabolism, signaling, and apoptosis. p62 is best known for its role in clearing protein aggregates via aggrephagy, but it has recently emerged as a receptor for other forms of selective autophagy such as mitophagy and lipophagy. Notably, p62 has context-dependent impacts on organismal aging and turnover of p62 usually reflects active proteostasis. In this review, we highlight recent advances in understanding the role of p62 in coordinating the ubiquitin-proteasome system and autophagy. We also discuss positive and negative effects of p62 on proteostatic status and their implications on aging and neurodegeneration. Finally, we relate the link between defective p62 and diseases of aging and examine the utility of targeting this multifaceted protein to achieve proteostatic benefits.
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Affiliation(s)
| | | | - Louis R. Lapierre
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, United States
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23
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Baskoylu SN, Chapkis N, Unsal B, Lins J, Schuch K, Simon J, Hart AC. Disrupted autophagy and neuronal dysfunction in C. elegans knockin models of FUS amyotrophic lateral sclerosis. Cell Rep 2022; 38:110195. [PMID: 35081350 DOI: 10.1016/j.celrep.2021.110195] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/01/2021] [Accepted: 12/10/2021] [Indexed: 11/18/2022] Open
Abstract
How mutations in FUS lead to neuronal dysfunction in amyotrophic lateral sclerosis (ALS) patients remains unclear. To examine mechanisms underlying ALS FUS dysfunction, we generate C. elegans knockin models using CRISPR-Cas9-mediated genome editing, creating R524S and P525L ALS FUS models. Although FUS inclusions are not detected, ALS FUS animals show defective neuromuscular function and locomotion under stress. Unlike animals lacking the endogenous FUS ortholog, ALS FUS animals have impaired neuronal autophagy and increased SQST-1 accumulation in motor neurons. Loss of sqst-1, the C. elegans ortholog for ALS-linked, autophagy adaptor protein SQSTM1/p62, suppresses both neuromuscular and stress-induced locomotion defects in ALS FUS animals, but does not suppress neuronal autophagy defects. Therefore, autophagy dysfunction is upstream of, and not dependent on, SQSTM1 function in ALS FUS pathogenesis. Combined, our findings demonstrate that autophagy dysfunction likely contributes to protein homeostasis and neuromuscular defects in ALS FUS knockin animals.
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Affiliation(s)
- Saba N Baskoylu
- Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA
| | - Natalie Chapkis
- Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA
| | - Burak Unsal
- Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA; Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey
| | - Jeremy Lins
- Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA
| | - Kelsey Schuch
- Department of Molecular Biology, Cellular Biology & Biochemistry, Brown University, Providence, RI 02906, USA
| | - Jonah Simon
- Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA
| | - Anne C Hart
- Department of Neuroscience and the Robert J. & Nancy D. Carney Institute for Brain Sciences, Brown University, Providence, RI 02906, USA.
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24
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Autophagy facilitates age-related cell apoptosis-a new insight from senile cataract. Cell Death Dis 2022; 13:37. [PMID: 35013122 PMCID: PMC8748728 DOI: 10.1038/s41419-021-04489-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/23/2021] [Accepted: 12/14/2021] [Indexed: 12/15/2022]
Abstract
Age-related cell loss underpins many senescence-associated diseases. Apoptosis of lens epithelial cells (LECs) is the important cellular basis of senile cataract resulted from prolonged exposure to oxidative stress, although the specific mechanisms remain elusive. Our data indicated the concomitance of high autophagy activity, low SQSTM1/p62 protein level and apoptosis in the same LEC from senile cataract patients. Meanwhile, in primary cultured LECs model, more durable autophagy activation and more obvious p62 degradation under oxidative stress were observed in LECs from elder healthy donors, compared with that from young healthy donors. Using autophagy-deficiency HLE-B3 cell line, autophagy adaptor p62 was identified as the critical scaffold protein sustaining the pro-survival signaling PKCι-IKK-NF-κB cascades, which antagonized the pro-apoptotic signaling. Moreover, the pharmacological inhibitor of autophagy, 3-MA, significantly inhibited p62 degradation and rescued oxidative stress-induced apoptosis in elder LECs. Collectively, this study demonstrated that durable activation of autophagy promoted age-related cell death in LECs. Our work contributes to better understanding the pathogenesis of senescence-associated diseases.
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25
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Shilovsky GA. Lability of the Nrf2/Keap/ARE Cell Defense System in Different Models of Cell Aging and Age-Related Pathologies. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:70-85. [PMID: 35491021 DOI: 10.1134/s0006297922010060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 06/14/2023]
Abstract
The level of oxidative stress in an organism increases with age. Accumulation of damages resulting in the disruption of genome integrity can be the cause of many age-related diseases and appearance of phenotypic and physiological signs of aging. In this regard, the Nrf2 system, which regulates expression of numerous enzymes responsible for the antioxidant defense and detoxification, is of great interest. This review summarizes and analyzes the data on the age-related changes in the Nrf2 system in vivo and in vitro in various organs and tissues. Analysis of published data suggests that the capacity for Nrf2 activation (triggered by the increased level of oxidative stress) steadily declines with age. At the same time, changes in the Nrf2 activity under the stress-free conditions do not have such unambiguous directionality; in many studies, these changes were statistically insignificant, although it is commonly accepted that the level of oxidative stress steadily increases with aging. This review examines the role of cell regulatory systems limiting the ability of Nrf2 to respond to oxidative stress. Senescent cells are extremely susceptible to the oxidative damage due to the impaired Nrf2 signaling. Activation of the Nrf2 pathway is a promising target for new pharmacological or genetic therapeutic strategies. Suppressors of the Nrf2 expression, such as Keap1, GSK3, c-Myc, and Bach1, may contribute to the age-related impairments in the induction of Nrf2-regulated antioxidant genes. Understanding the mechanisms of regulatory cascades linking the programs responsible for the maintenance of homeostasis and cell response to the oxidative stress will contribute to the elucidation of molecular mechanisms underlying aging and longevity.
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Affiliation(s)
- Gregory A Shilovsky
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
- Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, 127051, Russia
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26
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Wang L, Howell MEA, Sparks-Wallace A, Zhao J, Hensley CR, Nicksic CA, Horne SR, Mohr KB, Moorman JP, Yao ZQ, Ning S. The Ubiquitin Sensor and Adaptor Protein p62 Mediates Signal Transduction of a Viral Oncogenic Pathway. mBio 2021; 12:e0109721. [PMID: 34488443 PMCID: PMC8546576 DOI: 10.1128/mbio.01097-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/11/2021] [Indexed: 02/04/2023] Open
Abstract
The Epstein-Barr virus (EBV) protein LMP1 serves as a paradigm that engages complicated ubiquitination-mediated mechanisms to activate multiple transcription factors. p62 is a ubiquitin sensor and a signal-transducing adaptor that has multiple functions in diverse contexts. However, the interaction between p62 and oncogenic viruses is poorly understood. We recently reported a crucial role for p62 in oncovirus-mediated oxidative stress by acting as a selective autophagy receptor. In this following pursuit, we further discovered that p62 is upregulated in EBV type 3 compared to type 1 latency, with a significant contribution from NF-κB and AP1 activities downstream of LMP1 signaling. In turn, p62 participates in LMP1 signal transduction through its interaction with TRAF6, promoting TRAF6 ubiquitination and activation. As expected, short hairpin RNA (shRNA)-mediated knockdown (KD) of p62 transcripts reduces LMP1-TRAF6 interaction and TRAF6 ubiquitination, as well as p65 nuclear translocation, which was assessed by Amnis imaging flow cytometry. Strikingly, LMP1-stimulated NF-κB, AP1, and Akt activities are all markedly reduced in p62-/- mouse embryo fibroblasts (MEFs) and in EBV-negative Burkitt's lymphoma (BL) cell lines with CRISPR-mediated knockout (KO) of the p62-encoding gene. However, EBV-positive BL cell lines (type 3 latency) with CRISPR-mediated KO of the p62-encoding gene failed to survive. In consequence, shRNA-mediated p62 KD impairs the ability of LMP1 to regulate its target gene expression, promotes etoposide-induced apoptosis, and reduces the proliferation of lymphoblastic cell lines (LCLs). These important findings have revealed a previously unrecognized novel role for p62 in EBV latency and oncogenesis, which advances our understanding of the mechanism underlying virus-mediated oncogenesis. IMPORTANCE As a ubiquitin sensor and a signal-transducing adaptor, p62 is crucial for NF-κB activation, which involves the ubiquitin machinery, in diverse contexts. However, whether p62 is required for EBV LMP1 activation of NF-κB is an open question. In this study, we provide evidence that p62 is upregulated in EBV type 3 latency and, in turn, p62 mediates LMP1 signal transduction to NF-κB, AP1, and Akt by promoting TRAF6 ubiquitination and activation. In consequence, p62 deficiency negatively regulates LMP1-mediated gene expression, promotes etoposide-induced apoptosis, and reduces the proliferation of LCLs. These important findings identified p62 as a novel signaling component of the key viral oncogenic signaling pathway.
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Affiliation(s)
- Ling Wang
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Mary E. A. Howell
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Ayrianna Sparks-Wallace
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Juan Zhao
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Culton R. Hensley
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Camri A. Nicksic
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Shanna R. Horne
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Kaylea B. Mohr
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Jonathan P. Moorman
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- HCV/HIV Program, James H Quillen VA Medical Center, Johnson City, Tennessee, USA
| | - Zhi Q. Yao
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- HCV/HIV Program, James H Quillen VA Medical Center, Johnson City, Tennessee, USA
| | - Shunbin Ning
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
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27
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Mao C, Xu X, Ding Y, Xu N. Optimization of BCG Therapy Targeting Neutrophil Extracellular Traps, Autophagy, and miRNAs in Bladder Cancer: Implications for Personalized Medicine. Front Med (Lausanne) 2021; 8:735590. [PMID: 34660642 PMCID: PMC8514698 DOI: 10.3389/fmed.2021.735590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/05/2021] [Indexed: 01/07/2023] Open
Abstract
Bladder cancer (BC) is the ninth most common cancer and the thirteenth most common cause of mortality worldwide. Bacillus Calmette Guerin (BCG) instillation is a common treatment option for BC. BCG therapy is associated with the less adversary effects, compared to chemotherapy, radiotherapy, and other conventional treatments. BCG could inhibit the progression and recurrence of BC by triggering apoptosis pathways, arrest cell cycle, autophagy, and neutrophil extracellular traps (NETs) formation. However, BCG therapy is not efficient for metastatic cancer. NETs and autophagy were induced by BCG and help to suppress the growth of tumor cells especially in the primary stages of BC. Activated neutrophils can stimulate autophagy pathway and release NETs in the presence of microbial pathogenesis, inflammatory agents, and tumor cells. Autophagy can also regulate NETs formation and induce production of reactive oxygen species (ROS) and NETs. Moreover, miRNAs are important regulator of gene expression. These small non-coding RNAs are also considered as an essential factor to control the levels of tumor development. However, the interaction between BCG and miRNAs has not been well-understood yet. Therefore, the present study discusses the roles of miRNAs in regulations of autophagy and NETs formation in BCG therapy in the treatment of BC. The roles of autophagy and NETs formation in BC treatment and efficiency of BCG are also discussed.
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Affiliation(s)
- Chenyu Mao
- Department of Medical Oncology Cancer Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xin Xu
- Department of Medical Oncology Cancer Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yongfeng Ding
- Department of Medical Oncology Cancer Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Nong Xu
- Department of Medical Oncology Cancer Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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28
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Lu J, Zhao Y, Liu M, Lu J, Guan S. Toward improved human health: Nrf2 plays a critical role in regulating ferroptosis. Food Funct 2021; 12:9583-9606. [PMID: 34542140 DOI: 10.1039/d1fo01036k] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ferroptosis is a recently defined type of regulated cell death caused by an excess iron-dependent accumulation of lipid peroxides and is morphologically and biochemically distinct from other types of cell death. Notably, Nrf2 is identified to exquisitely modulate ferroptosis due to its ability to target a host of ferroptosis cascade genes, which places Nrf2 in the pivotal position of ferroptosis. This paper reviews the regulation effect of Nrf2 on ferroptosis, different activation mechanisms of Nrf2 as well as the relevance of the Nrf2-ferroptosis axis in diseases, and finally summarizes foods with beneficial effects in ferroptosis via the Nrf2 pathway and aims to serve as a reference for follow-up studies of food functions related to Nrf2, ferroptosis, and human health.
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Affiliation(s)
- Jing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China. .,Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, People's Republic of China
| | - Yanan Zhao
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
| | - Meitong Liu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
| | - Jianing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
| | - Shuang Guan
- College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China. .,Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, People's Republic of China
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29
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Xu C, Wu J, Wu Y, Ren Z, Yao Y, Chen G, Fang EF, Noh JH, Liu YU, Wei L, Chen X, Sima J. TNF-α-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG. Theranostics 2021; 11:9452-9469. [PMID: 34646380 PMCID: PMC8490500 DOI: 10.7150/thno.62376] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 09/05/2021] [Indexed: 12/29/2022] Open
Abstract
Background: Neuronal death is a major hallmark of Alzheimer's disease (AD). Necroptosis, as a programmed necrotic process, is activated in AD. However, what signals and factors initiate necroptosis in AD is largely unknown. Methods: We examined the expression levels of critical molecules in necroptotic signaling pathway by immunohistochemistry (IHC) staining and immunoblotting using brain tissues from AD patients and AD mouse models of APP/PS1 and 5×FAD. We performed brain stereotaxic injection with recombinant TNF-α, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 mice. For in vitro studies, we used TNF-α combined with zVAD-fmk and Smac mimetic to establish neuronal necroptosis models and utilized pharmacological or molecular biological approaches to study the signaling pathways. Results: We find that activated neuronal necroptosis is dependent on upstream TNF-α/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-α stimulation, accumulated p62 recruits RIPK1 and induces its self-oligomerization, and activates downstream RIPK1/RIPK3/MLKL cascade, leading to neuronal necroptosis. Ectopic accumulation of p62 is caused by impaired autophagy flux, which is mediated by UVRAG downregulation during the TNF-α-promoted necroptosis. Notably, UVRAG overexpression inhibits neuronal necroptosis in cell and mouse models of AD. Conclusions: We identify a finely controlled regulation of neuronal necroptosis in AD by coordinated TNF-α signaling, RIPK1/3 activity and autophagy machinery. Strategies that could fine-tune necroptosis and autophagy may bring in promising therapeutics for AD.
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Affiliation(s)
- Chong Xu
- Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Jialin Wu
- Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Yiqun Wu
- Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Zhichu Ren
- Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuyuan Yao
- Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Guobing Chen
- Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Evandro F. Fang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
- The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway
| | - Ji Heon Noh
- Department of Biochemistry, Chungnam National University, Daehak-ro 99, Yuseong-gu, Daejeon
| | - Yong U. Liu
- Laboratory for Neuroscience in Health and Disease, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China
| | - Libin Wei
- Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, 210009, China
| | - Xijing Chen
- Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Jian Sima
- Laboratory of Aging Neuroscience and Neuropharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
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30
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González M, Ovejero-Sánchez M, Vicente-Blázquez A, Medarde M, González-Sarmiento R, Peláez R. Methoxy and bromo scans on N-(5-methoxyphenyl) methoxybenzenesulphonamides reveal potent cytotoxic compounds, especially against the human breast adenocarcinoma MCF7 cell line. J Enzyme Inhib Med Chem 2021; 36:1029-1047. [PMID: 34107837 PMCID: PMC8205030 DOI: 10.1080/14756366.2021.1925265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Thirty seven N-(5-methoxyphenyl)-4-methoxybenzenesulphonamide with methoxy or/and bromo substitutions (series 1-4) and with different substituents on the sulphonamide nitrogen have been synthesised. 21 showed sub-micromolar cytotoxicity against HeLa and HT-29 human tumour cell lines, and were particularly effective against MCF7. The most potent series has 2,5-dimethoxyanilines, especially the 4-brominated compounds 23–25. The active compounds inhibit microtubular protein polymerisation at micromolar concentrations, thus pointing at tubulin as the target. Co-treatment with the MDR inhibitor verapamil suggests that they are not MDR substrates. Compound 25 showed nanomolar antiproliferative potency. It severely disrupts the microtubule network in cells and arrests cells at the G2/M cell-cycle phase, thus confirming tubulin targeting. 25 triggered apoptotic cell death, and induced autophagy. Docking studies suggest binding in a distinct way to the colchicine site. These compounds are promising new antitumor agents acting on tubulin.
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Affiliation(s)
- Myriam González
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.,Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain
| | - María Ovejero-Sánchez
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.,Unidad de Medicina Molecular, Departamento de Medicina, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain.,Laboratorio de Diagnóstico en Cáncer Hereditario, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Salamanca, Spain
| | - Alba Vicente-Blázquez
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.,Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain
| | - Manuel Medarde
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.,Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain
| | - Rogelio González-Sarmiento
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.,Unidad de Medicina Molecular, Departamento de Medicina, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain.,Laboratorio de Diagnóstico en Cáncer Hereditario, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Salamanca, Spain
| | - Rafael Peláez
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain.,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.,Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Salamanca, Spain
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31
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Yang HL, Liu HW, Shrestha S, Thiyagarajan V, Huang HC, Hseu YC. Antrodia salmonea induces apoptosis and enhances cytoprotective autophagy in colon cancer cells. Aging (Albany NY) 2021; 13:15964-15989. [PMID: 34031264 PMCID: PMC8266357 DOI: 10.18632/aging.203019] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/05/2021] [Indexed: 04/07/2023]
Abstract
A traditional Chinese medicinal fungus, Antrodia salmonea (AS), with antioxidant properties is familiar in Taiwan but anti-cancer activity of AS in human colon cancer is ambiguous. Hence, we explored the anti-cancer activity of AS in colon cancer cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that AS showed a remarkable effect on cell viability in colon cancer cells; SW620, HCT116, and HT29. Annexin V/propidium iodide (PI) stained cells indicated that AS induced both early/late apoptosis in SW620 cells. Additionally, cells treated with AS induced caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, mitochondrial dysfunction, and Bcl-2 associated X (Bax)/B-cell lymphoma (Bcl-2) dysregulation. Microtubule- associated protein 1A/1B-light chain 3B (LC3-II) accumulation, sequestosome 1 (p62/SQSTM1) activation, autophagy related 4B cysteine peptidase (ATG4B) inactivation, acidic vesicular organelles (AVOs) formation, and Beclin-1/Bcl-2 dysregulation revealed that AS-induced autophagy. Interestingly, cells pretreated with 3-methyladenine (3-MA) strengthened AS-induced caspase-3/apoptosis. Suppression of apoptosis by z-Val-Ala-Asp fluoromethyl ketone (Z-VAD-FMK) did not however block AS-induced autophagy, suggesting that autophagy was not attenuated by the AS-induced apoptosis. Application of N-acetylcysteine (NAC) prevented AS-induced cell death, caspase-3 activation, LC3-II accumulation, and AVOs formation, indicating that AS-induced apoptosis and autophagy was mediated by reactive oxygen species (ROS). Furthermore, AS-induced cytoprotective autophagy and apoptosis through extracellular signal-regulated kinase (ERK) signaling cascades. Moreover, in vivo data disclosed that AS inhibited colitis-associated tumorigenesis in azoxymethane (AOM)-dextran sodium sulphate (DSS)-treated mice. For the first time, we report the anti-cancer properties of this potentially advantageous mushroom for the treatment of human colon cancer.
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Affiliation(s)
- Hsin-Ling Yang
- Institute of Nutrition, College of Health Care, China Medical University, Taichung 40402, Taiwan
| | - Hui-Wen Liu
- Institute of Nutrition, College of Health Care, China Medical University, Taichung 40402, Taiwan
| | - Sirjana Shrestha
- Institute of Nutrition, College of Health Care, China Medical University, Taichung 40402, Taiwan
| | | | - Hui-Chi Huang
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
| | - You-Cheng Hseu
- Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung 40402, Taiwan
- Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan
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Dong W, Liu G, Zhang K, Tan Y, Zou H, Yuan Y, Gu J, Song R, Zhu J, Liu Z. Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 214:112058. [PMID: 33714136 DOI: 10.1016/j.ecoenv.2021.112058] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/04/2021] [Accepted: 02/10/2021] [Indexed: 06/12/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor of great concern which is widely involved in physiological and pathological processes of the organism, but the role and regulatory mechanism of Nrf2 in kidney exposed to cadmium (Cd) remain largely unknown. Here we demonstrated that Cd exposure induced injury in primary rat proximal tubular (rPT) cells and NRK-52E cell line, which was accompanied by autophagic flux blockade and subsequent accumulation of p62. Cd-activated nucleus translocation of Nrf2 depended on p62, which promoted antioxidant genes transcription, but it failed to against Cd-induced cell injury and ultimately succumbed to Cd toxicity. CDDO Methyl Ester (CDDO-ME) or ML385 treatment aggravated or alleviated rPT cells injury induced by Cd respectively, indicating that Nrf2 nucleus translocation played a negative role during Cd-induced rPT cells injury. Phosphorylation of 5' AMP-activated protein kinase (AMPK) decreased together with enhanced Nrf2 nucleus translocation in rPT cells exposed to Cd. Dephosphorylation of AMPK induced by Cd were facilitated or restored by CDDO-ME or ML385 treatment, which confirmed AMPK is a downstream factor of Nrf2. Simultaneously, CDDO-ME further enhanced Phosphorylation of mTOR and AKT which increased during Cd exposure. While, Cd-induced phosphorylation of mTOR and AKT were reversed by ML385 treatment. These results illustrated that Cd mediated Nrf2 nucleus translocation depends on p62 accumulation which results from autophagic flux inhibition. The enhanced nucleus translocation of Nrf2 suppresses phosphorylation of AMPK to inactivate AKT/mTOR signaling, and results in rPT cells injury finally.
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Affiliation(s)
- Wenxuan Dong
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China
| | - Gang Liu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China.
| | - Kanglei Zhang
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China
| | - Yun Tan
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China
| | - Jiaqiao Zhu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, People's Republic of China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, People's Republic of China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China.
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Yu F, Ma R, Liu C, Zhang L, Feng K, Wang M, Yin D. SQSTM1/p62 Promotes Cell Growth and Triggers Autophagy in Papillary Thyroid Cancer by Regulating the AKT/AMPK/mTOR Signaling Pathway. Front Oncol 2021; 11:638701. [PMID: 33937040 PMCID: PMC8082099 DOI: 10.3389/fonc.2021.638701] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/12/2021] [Indexed: 01/01/2023] Open
Abstract
Background Thyroid cancer is one of the most common endocrine malignancies worldwide, and papillary thyroid cancer (PTC) is the most common pathologic type of thyroid cancer. SQSTM1/p62 activity mediates different biological functions. This study aimed to investigate the effect of SQSTM1/p62, a multifunctional receptor, on biological function and autophagy characteristics in the human PTC cell line TPC-1. Methods A total of 105 primary PTC samples and matched adjacent normal thyroid tissue samples were obtained to evaluate the expression of p62 in clinical patients. A similar p62 expression pattern was found in PTC cell lines and normal human thyroid follicular epithelial cells. To evaluate the effect of SQSTM1/p62 on TPC-1 cells, we constructed the p62 knockout cell line p62-KO-TPC-1. Cell proliferation, cell cycle, and cell apoptosis were analyzed by colony formation tests, Cell Counting Kit-8 (CCK-8) assays and flow cytometry in vitro. TPC-1 and p62-KO-TPC-1 human PTC cell lines in the logarithmic growth phase were subcutaneously implanted into BALB/c nude mice to verify their proliferation effect in vivo. Furthermore, western blotting and immunohistochemistry (IHC) were used to detect the expression of AKT/AMPK/mTOR signaling pathway-related proteins. Results Overall, p62 expression was higher in tumor tissues than in normal tissues in 73 of 105 PTC patients (69.5%). The expression level of p62 in the PTC cell line was higher than that in the normal thyroid cell line. Our data indicated that in vitro, p62 deficiency could decrease the number of colonies, inhibit cell growth and the cell cycle, and induce apoptosis. Tumor xenograft experiments in BALB/c nude mice corroborated these findings. Moreover, the molecular mechanism was explored by western blotting, and we found that the AMPK/AKT/mTOR pathway was involved. Conclusions The results indicate that p62 might mediate cell autophagy and apoptosis in TPC-1 cells via the AMPK/AKT/mTOR pathway and could be used as a potential therapeutic approach for PTC.
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Affiliation(s)
- Fangqin Yu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Runsheng Ma
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chenguang Liu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lele Zhang
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kaixiang Feng
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Meiqi Wang
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Detao Yin
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Huang Y, Jin G, Zhan QL, Tian Y, Shen L. Adult-onset neuronal intranuclear inclusion disease, with both stroke-like onset and encephalitic attacks: a case report. BMC Neurol 2021; 21:142. [PMID: 33789591 PMCID: PMC8011180 DOI: 10.1186/s12883-021-02164-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/22/2021] [Indexed: 12/16/2022] Open
Abstract
Background Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease, the clinical manifestations of which are complex and easily misdiagnosed. NIID clinical characteristics are varied, affecting the central and peripheral nervous systems and autonomic nerves. In this study, we present an NIID case with both stroke-like onset and encephalitic attacks, which is a rare case report. Case presentation A 68-year-old Chinese female presented with sudden aphasia and limb hemiplegia as the first symptoms, as well as fever, cognitive impairment and mental irritability from encephalitic attacks. During hospitalization, a brain magnetic resonance imaging (MRI) examination detected high signal intensity from diffusion-weighted imaging (DWI) of the bilateral frontal grey matter-white matter junction. Electrophysiological tests revealed the main site of injury was at the myelin sheath in the motor nerves. A skin biopsy revealed eosinophilic spherical inclusion bodies in the nuclei of small sweat gland cells, fibroblasts and fat cells, whilst immunohistochemistry revealed that p62 and ubiquitin antibodies were positive. From genetic analyses, the patient was not a carrier of the fragile X mental retardation 1 (FMR1) permutation, but repeated GGC sequences in the NOTCH2NLC gene confirmed an NIID diagnosis. Through antipsychotic and nutritional support therapy, the patient’s symptoms were completely relieved within 3 weeks. Conclusions This report of an NIID case with both stroke-like onset and encephalitic attacks provides new information for NIID diagnoses, and a comprehensive classification of clinical characteristics.
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Affiliation(s)
- Ying Huang
- Department of Neurology, Chongqing Renji Hospital, University of Chinese Academy of Sciences, Chongqing, 400062, China.
| | - Ge Jin
- Department of Neurology, Chongqing Renji Hospital, University of Chinese Academy of Sciences, Chongqing, 400062, China
| | - Qun-Ling Zhan
- Department of Neurology, Chongqing Renji Hospital, University of Chinese Academy of Sciences, Chongqing, 400062, China
| | - Yun Tian
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Lu Shen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
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Hurley EP, Staveley BE. Inhibition of Ref(2)P, the Drosophila homologue of the p62/SQSTM1 gene, increases lifespan and leads to a decline in motor function. BMC Res Notes 2021; 14:53. [PMID: 33557921 PMCID: PMC7871602 DOI: 10.1186/s13104-021-05462-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 01/22/2021] [Indexed: 11/30/2022] Open
Abstract
Objective Sequestosome 1 (p62/SQSTM1) is a multifunctional scaffold/adaptor protein encoded by the p62/SQSTM1 gene with function in cellular homeostasis. Mutations in the p62/SQSTM1 gene have been known to be associated with patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson disease (PD). The aim of the present study was to create a novel model of human neurogenerative disease in Drosophila melanogaster by altering the expression of Ref(2)P, the Drosophila orthologue of the human p62/SQSTM1 gene. Ref(2)P expression was altered in all neurons, the dopaminergic neurons and in the motor neurons, with longevity and locomotor function assessed over time. Results Inhibition of Ref(2)P resulted in a significantly increased median lifespan in the motor neurons, followed by a severe decline in motor skills. Inhibition of Ref(2)P in the dopaminergic neurons resulted in a significant, but minimal increase in median lifespan, accompanied by a drastic decline in locomotor function. Inhibition of Ref(2)P in the ddc-Gal4-expressing neurons resulted in a significant increase in median lifespan, while dramatically reducing motor function.
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Affiliation(s)
- Emily P Hurley
- Department of Biology, Memorial University of Newfoundland, St. Johns', NL, A1B 3X9, Canada
| | - Brian E Staveley
- Department of Biology, Memorial University of Newfoundland, St. Johns', NL, A1B 3X9, Canada.
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36
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Pharmacological Inhibition of O-GlcNAc Transferase Promotes mTOR-Dependent Autophagy in Rat Cortical Neurons. Brain Sci 2020; 10:brainsci10120958. [PMID: 33317171 PMCID: PMC7763293 DOI: 10.3390/brainsci10120958] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 11/30/2020] [Accepted: 12/07/2020] [Indexed: 12/18/2022] Open
Abstract
O-GlcNAc transferase (OGT) is a ubiquitous enzyme that regulates the addition of β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of target proteins. Autophagy is a cellular process of self-digestion, in which cytoplasmic resources, such as aggregate proteins, toxic compounds, damaged organelles, mitochondria, and lipid molecules, are degraded and recycled. Here, we examined how three different OGT inhibitors, alloxan, BXZ2, and OSMI-1, modulate O-GlcNAcylation in rat cortical neurons, and their autophagic effects were determined by immunoblot and immunofluorescence assays. We found that the treatment of cortical neurons with an OGT inhibitor decreased O-GlcNAcylation levels and increased LC3-II expression. Interestingly, the pre-treatment with rapamycin, an mTOR inhibitor, further increased the expression levels of LC3-II induced by OGT inhibition, implicating the involvement of mTOR signaling in O-GlcNAcylation-dependent autophagy. In contrast, OGT inhibitor-mediated autophagy was significantly attenuated by 3-methyladenine (3-MA), a blocker of autophagosome formation. However, when pre-treated with chloroquine (CQ), a lysosomotropic agent and a late-stage autophagy inhibitor, OGT inhibitors significantly increased LC3-II levels along with LC3 puncta formation, indicating the stimulation of autophagic flux. Lastly, we found that OGT inhibitors significantly decreased the levels of the autophagy substrate p62/SQSTM1 while increasing the expression of lysosome-associated membrane protein 1 (LAMP1). Together, our study reveals that the modulation of O-GlcNAcylation by OGT inhibition regulates mTOR-dependent autophagy in rat cortical neurons.
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Chung LH, Liu ST, Huang SM, Salter DM, Lee HS, Hsu YJ. High phosphate induces skeletal muscle atrophy and suppresses myogenic differentiation by increasing oxidative stress and activating Nrf2 signaling. Aging (Albany NY) 2020; 12:21446-21468. [PMID: 33136552 PMCID: PMC7695395 DOI: 10.18632/aging.103896] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022]
Abstract
Skeletal muscle wasting represents both a common phenotype of aging and a feature of pathological conditions such as chronic kidney disease (CKD). Although both clinical data and genetic experiments in mice suggest that hyperphosphatemia accelerates muscle wasting, the underlying mechanism remains unclear. Here, we showed that inorganic phosphate (Pi) dose-dependently decreases myotube size, fusion index, and myogenin expression in mouse C2C12 skeletal muscle cells. These changes were accompanied by increases in reactive oxygen species (ROS) production and Nrf2 and p62 expression, and reductions in mitochondrial membrane potential (MMP) and Keap1 expression. Inhibition of Pi entry, cytosolic ROS production, or Nrf2 activation reversed the effects of high Pi on Nrf2, p62, and myogenin expression. Overexpression of Nrf2 respectively increased and decreased the promoter activity of p62-Luc and myogenin-Luc reporters. Analysis of nuclear extracts from gastrocnemius muscles from mice fed a high-Pi (2% Pi) diet showed increased Nrf2 phosphorylation in sham-operated and 5/6 nephrectomized (CKD) mice, and both increased p62 phosphorylation and decreased myogenin expression in CKD mice. These data suggest that high Pi suppresses myogenic differentiation in vitro and promotes muscle atrophy in vivo through oxidative stress-mediated protein degradation and both canonical (ROS-mediated) and non-canonical (p62-mediated) activation of Nrf2 signaling.
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Affiliation(s)
- Lin-Huei Chung
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,Division of Nephrology, Department of Internal Medicine, Yuan Rung Hospital, Changhua, Taiwan
| | - Shu-Ting Liu
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Shih-Ming Huang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Donald M Salter
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Herng-Sheng Lee
- Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Yu-Juei Hsu
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.,Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Zhou H, Zhang L, Li Y, Wu G, Zhu H, Zhang H, Su JK, Guo L, Zhou Q, Xiong F, Yu Q, Yang P, Zhang S, Cai J, Wang CY. Cigarette smoke extract stimulates bronchial epithelial cells to undergo a SUMOylation turnover. BMC Pulm Med 2020; 20:276. [PMID: 33097022 PMCID: PMC7584069 DOI: 10.1186/s12890-020-01300-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 09/21/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) characterized by the airway and lung inflammation, is a leading cause of morbidity and mortality worldwide, especially among smokers over 40 years of age and individuals exposed to biomass smoke. Although the detailed mechanisms of this disease remain elusive, there is feasible evidence that protein posttranslational modifications (PTMs) may play a role in its pathoetiology. We thus conducted studies to dissect the effect of cigarette smoke extracts (CSE) on the change of SUMOylated substrates in human bronchial epithelial cells (HBEs). METHODS Samples were collected in HBEs with or without 24 h of CSE insult and then subjected to Western-blot and LC-MS/MS analysis. Subsequently, bioinformatic tools were used to analyze the data. The effect of SUMOylation on cytochrome P450 1A1 (CYP1A1) was evaluated by flow cytometry. RESULTS It was noted that CSE stimulated HBEs to undergo a SUMOylation turnover as evidenced by the changes of SUMOylated substrates and SUMOylation levels for a particular substrate. The SUMOylated proteins are relevant to the regulation of biological processes, molecular function and cellular components. Particularly, CSE stimulated a significant increase of SUMOylated CYP1A1, a critical enzyme involved in the induction of oxidative stress. CONCLUSIONS Our data provide a protein SUMOylation profile for better understanding of the mechanisms underlying COPD and support that smoking induces oxidative stress in HBEs, which may predispose to the development of COPD in clinical settings.
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Affiliation(s)
- Haifeng Zhou
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
| | - Lei Zhang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Li
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
| | - Guorao Wu
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - He Zhu
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
| | - Huilan Zhang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Kun Su
- The Technology Center, China Tobacco Jiangxi Industrial Co., Ltd., Nanchang High Technology Development Valley, Nanchang, 330096, China
| | - Lei Guo
- The Technology Center, China Tobacco Jiangxi Industrial Co., Ltd., Nanchang High Technology Development Valley, Nanchang, 330096, China
| | - Qing Zhou
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
| | - Fei Xiong
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
| | - Qilin Yu
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
| | - Ping Yang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
| | - Shu Zhang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China
| | - Jibao Cai
- The Technology Center, China Tobacco Jiangxi Industrial Co., Ltd., Nanchang High Technology Development Valley, Nanchang, 330096, China.
| | - Cong-Yi Wang
- The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Caidian, 431000, China.
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Murata D, Arai K, Iijima M, Sesaki H. Mitochondrial division, fusion and degradation. J Biochem 2020; 167:233-241. [PMID: 31800050 DOI: 10.1093/jb/mvz106] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 11/17/2019] [Indexed: 12/11/2022] Open
Abstract
The mitochondrion is an essential organelle for a wide range of cellular processes, including energy production, metabolism, signal transduction and cell death. To execute these functions, mitochondria regulate their size, number, morphology and distribution in cells via mitochondrial division and fusion. In addition, mitochondrial division and fusion control the autophagic degradation of dysfunctional mitochondria to maintain a healthy population. Defects in these dynamic membrane processes are linked to many human diseases that include metabolic syndrome, myopathy and neurodegenerative disorders. In the last several years, our fundamental understanding of mitochondrial fusion, division and degradation has been significantly advanced by high resolution structural analyses, protein-lipid biochemistry, super resolution microscopy and in vivo analyses using animal models. Here, we summarize and discuss this exciting recent progress in the mechanism and function of mitochondrial division and fusion.
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Affiliation(s)
- Daisuke Murata
- Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA
| | - Kenta Arai
- Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA
| | - Miho Iijima
- Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA
| | - Hiromi Sesaki
- Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA
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Ning S, Wang L. The Multifunctional Protein p62 and Its Mechanistic Roles in Cancers. Curr Cancer Drug Targets 2020; 19:468-478. [PMID: 30332964 PMCID: PMC8052633 DOI: 10.2174/1568009618666181016164920] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 08/17/2018] [Accepted: 09/28/2018] [Indexed: 12/16/2022]
Abstract
The multifunctional signaling hub p62 is well recognized as a ubiquitin sensor and a selective autophagy receptor. As a ubiquitin sensor, p62 promotes NFκB activation by facilitating TRAF6 ubiquitination and aggregation. As a selective autophagy receptor, p62 sorts ubiquitinated substrates including p62 itself for lysosome-mediated degradation. p62 plays crucial roles in myriad cellular processes including DNA damage response, aging/senescence, infection and immunity, chronic inflammation, and cancerogenesis, dependent on or independent of autophagy. Targeting p62-mediated autophagy may represent a promising strategy for clinical interventions of different cancers. In this review, we summarize the transcriptional and post-translational regulation of p62, and its mechanistic roles in cancers, with the emphasis on its roles in regulation of DNA damage response and its connection to the cGAS-STING-mediated antitumor immune response, which is promising for cancer vaccine design.
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Affiliation(s)
- Shunbin Ning
- Division of Infectious Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States.,Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States
| | - Ling Wang
- Division of Infectious Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States.,Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States
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Pérez‐Portela R, Riesgo A, Wangensteen OS, Palacín C, Turon X. Enjoying the warming Mediterranean: Transcriptomic responses to temperature changes of a thermophilous keystone species in benthic communities. Mol Ecol 2020; 29:3299-3315. [DOI: 10.1111/mec.15564] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 07/08/2020] [Accepted: 07/20/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Rocío Pérez‐Portela
- Department of Evolutionary Biology, Ecology and Environmental Sciences University of Barcelona, and Research Institute of Biodiversity (IRBIO) Barcelona Spain
- Center for Advanced Studies of Blanes (CEAB, CSIC) Girona Spain
| | - Ana Riesgo
- Department of Life Sciences The Natural History Museum London UK
| | - Owen S. Wangensteen
- Norwegian College of Fishery Science UiT The Arctic University of Norway Tromsø Norway
| | - Cruz Palacín
- Department of Evolutionary Biology, Ecology and Environmental Sciences University of Barcelona, and Research Institute of Biodiversity (IRBIO) Barcelona Spain
| | - Xavier Turon
- Center for Advanced Studies of Blanes (CEAB, CSIC) Girona Spain
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42
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Pérez-Plasencia C, López-Urrutia E, García-Castillo V, Trujano-Camacho S, López-Camarillo C, Campos-Parra AD. Interplay Between Autophagy and Wnt/β-Catenin Signaling in Cancer: Therapeutic Potential Through Drug Repositioning. Front Oncol 2020; 10:1037. [PMID: 33014767 PMCID: PMC7461967 DOI: 10.3389/fonc.2020.01037] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 05/26/2020] [Indexed: 12/20/2022] Open
Abstract
The widespread dysregulation that characterizes cancer cells has been dissected and many regulation pathways common to multiple cancer types have been described in depth. Wnt/β-catenin signaling and autophagy are among these principal pathways, which contribute to tumor growth and resistance to anticancer therapies. Currently, several therapeutic strategies that target either Wnt/β-catenin signaling or autophagy are in various stages of development. Targeted therapies that block specific elements that participate in both pathways; are subject to in vitro studies as well as pre-clinical and early clinical trials. Strikingly, drugs designed for other diseases also impact these pathways, which is relevant since they are already FDA-approved and sometimes even routinely used in the clinic. The main focus of this mini-review is to highlight the importance of drug repositioning to inhibit the Wnt/β-catenin and autophagy pathways, with an emphasis on the interplay between them. The data we found strongly suggested that this field is worth further examination.
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Affiliation(s)
- Carlos Pérez-Plasencia
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, Mexico
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - Eduardo López-Urrutia
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, Mexico
| | - Verónica García-Castillo
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, Mexico
| | - Samuel Trujano-Camacho
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico
| | - Alma D. Campos-Parra
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
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43
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Friesen EL, Zhang YT, Earnshaw R, De Snoo ML, O'Hara DM, Agapova V, Chau H, Ngana S, Chen KS, Kalia LV, Kalia SK. BAG5 Promotes Alpha-Synuclein Oligomer Formation and Functionally Interacts With the Autophagy Adaptor Protein p62. Front Cell Dev Biol 2020; 8:716. [PMID: 32850835 PMCID: PMC7417480 DOI: 10.3389/fcell.2020.00716] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 07/13/2020] [Indexed: 11/13/2022] Open
Abstract
Molecular chaperones are critical to maintaining intracellular proteostasis and have been shown to have a protective role against alpha-synuclein-mediated toxicity. Co-chaperone proteins regulate the activity of molecular chaperones and connect the chaperone network to protein degradation and cell death pathways. Bcl-2 associated athanogene 5 (BAG5) is a co-chaperone that modulates proteostasis by inhibiting the activity of Heat shock protein 70 (Hsp70) and several E3 ubiquitin ligases, resulting in enhanced neurodegeneration in models of Parkinson's disease (PD). Here we identify a novel interaction between BAG5 and p62/sequestosome-1 (SQSTM1), suggesting that BAG5 may bridge the chaperone network to autophagy-mediated protein degradation. We found that BAG5 enhanced the formation of pathogenic alpha-synuclein oligomers and regulated the levels and subcellular distribution of p62. These results extend the role of BAG5 in alpha-synuclein processing and intracellular proteostasis.
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Affiliation(s)
- Erik L Friesen
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Yu Tong Zhang
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Rebecca Earnshaw
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Mitch L De Snoo
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Darren M O'Hara
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Victoria Agapova
- Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Hien Chau
- Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Sophie Ngana
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Kevin S Chen
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada
| | - Lorraine V Kalia
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada.,Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Suneil K Kalia
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Genetics and Development, Krembil Research Institute, Toronto, ON, Canada.,Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
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44
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Zhang ZY, Guo S, Zhao R, Ji ZP, Zhuang ZN. Clinical significance of SQSTM1/P62 and nuclear factor-κB expression in pancreatic carcinoma. World J Gastrointest Oncol 2020; 12:719-731. [PMID: 32864040 PMCID: PMC7428796 DOI: 10.4251/wjgo.v12.i7.719] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/03/2020] [Accepted: 05/27/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Overexpression of SQSTM1 (sequestosome 1, P62) and nuclear factor-κB (NF-κB) plays an important role in the invasion and metastasis of a variety of malignant tumors.
AIM To explore the expression of P62 and NF-κB in pancreatic cancer and their relationship with clinicopathological features.
METHODS The expression levels of P62 and NF-κB were analyzed by immunohistochemistry with a tissue chip containing 40 cases of human pancreatic carcinoma. Then we analyzed the correlation among P62 expression, phospho-P65 expression, and clinicopathological features of pancreatic carcinoma samples.
RESULTS P62 expression was mainly observed in the cytoplasm of pancreatic carcinoma cells. Phosphorylated P65 (phospho-P65) was mainly expressed in the nucleus and cytoplasm of pancreatic carcinoma cells. There was a significant difference in P62 expression among T stages. And a significant difference in phosphor-P65 expression among pathology types was noted. In the cases with strongly positive P62 expression, significant differences were found in age. And there were significant differences in T stage and tumor-node-metastasis stage in the cases with strongly positive phosphor-P65 expression.
CONCLUSION In pancreatic carcinoma, P62 expression is significantly correlated with T stage. It may be a valuable malignant indicator for human pancreatic carcinoma.
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Affiliation(s)
- Zhao-Yang Zhang
- Department of Emergency Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Sen Guo
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Rui Zhao
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, Shandong Province, China
| | - Zhi-Peng Ji
- Department of General Surgery, Second Affiliated Hospital of Shandong University, Jinan 250033, Shandong Province, China
| | - Zhuo-Nan Zhuang
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102200, China
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45
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Gloeckner CJ, Porras P. Guilt-by-Association - Functional Insights Gained From Studying the LRRK2 Interactome. Front Neurosci 2020; 14:485. [PMID: 32508578 PMCID: PMC7251075 DOI: 10.3389/fnins.2020.00485] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 04/20/2020] [Indexed: 12/11/2022] Open
Abstract
The Parkinson's disease-associated Leucine-rich repeat kinase 2 (LRRK2) is a complex multi-domain protein belonging to the Roco protein family, a unique group of G-proteins. Variants of this gene are associated with an increased risk of Parkinson's disease. Besides its well-characterized enzymatic activities, conferred by its GTPase and kinase domains, and a central dimerization domain, it contains four predicted repeat domains, which are, based on their structure, commonly involved in protein-protein interactions (PPIs). In the past decades, tremendous progress has been made in determining comprehensive interactome maps for the human proteome. Knowledge of PPIs has been instrumental in assigning functions to proteins involved in human disease and helped to understand the connectivity between different disease pathways and also significantly contributed to the functional understanding of LRRK2. In addition to an increased kinase activity observed for proteins containing PD-associated variants, various studies helped to establish LRRK2 as a large scaffold protein in the interface between cytoskeletal dynamics and the vesicular transport. This review first discusses a number of specific LRRK2-associated PPIs for which a functional consequence can at least be speculated upon, and then considers the representation of LRRK2 protein interactions in public repositories, providing an outlook on open research questions and challenges in this field.
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Affiliation(s)
- Christian Johannes Gloeckner
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- Center for Ophthalmology, Institute for Ophthalmic Research, Core Facility for Medical Bioanalytics, University of Tübingen, Tübingen, Germany
- Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Pablo Porras
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cherry Hinton, United Kingdom
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46
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The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. Nat Commun 2020; 11:2306. [PMID: 32385399 PMCID: PMC7211001 DOI: 10.1038/s41467-020-16230-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 04/16/2020] [Indexed: 12/31/2022] Open
Abstract
During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62−/− and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding. Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1α. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1α induction.
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47
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Shaik NA, Nasser KK, Alruwaili MM, Alallasi SR, Elango R, Banaganapalli B. Molecular modelling and dynamic simulations of sequestosome 1 (SQSTM1) missense mutations linked to Paget disease of bone. J Biomol Struct Dyn 2020; 39:2873-2884. [PMID: 32329415 DOI: 10.1080/07391102.2020.1758212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The Paget disease (PDB; OMIM is 167250) is a chronic bone disease caused by pathogenic mutations in Sequestome1/p62 (SQSTM1) gene. This study has aimed to interpret the relationship of PDB linked SQSTM1 mutations with protein structure and its molecular dynamic features. The disease causative missense mutations were initially collected, and then analyzed for their, exonic and domain distribution, impact on secondary and tertiary structures, and their ability on protein-ligand interactions, using a combination of systems biology approaches. Our results show that most PDB linked SQSTM1 missense mutations affect amino acid residues clustered within or near the UBA domain (aa 389-434), which participates in the ubiquitination of substrates. We also report that the majority mutations occurred in α-helices over β-strands but their effects on the secondary structure were mostly neutral. Global tertiary structure deviations were minimal; however, at amino acid residue level minor structural changes were evident. The molecular dynamics simulation analysis showed that both PB1 and UBA domains were under constant structural fluctuations resulting in closed form conformation of SQSMT1 protein structure, when it is bound to PRKCI ligand. We also found salt bridge conformation changes in the UBA domain of SQSTM1 mutants when they bound to the PRKCI interactor protein. This finding suggests the possibility that mutations in SQSTM1 could impair its ability to ubiquitinate the substrates, eventually affecting autophagy and apoptosis, especially in mature osteoclasts. This study presents the additional insight into structure and function relationship between SQSTM1 mutations and PDB pathogenesis. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Noor Ahmad Shaik
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Saudi Arabia.,Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Khalidah K Nasser
- Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Muteb Muidh Alruwaili
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Saudi Arabia
| | - Sami Raja Alallasi
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Saudi Arabia
| | - Ramu Elango
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Saudi Arabia.,Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Babajan Banaganapalli
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Saudi Arabia.,Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
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48
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Edwards G, Perkins GA, Kim KY, Kong Y, Lee Y, Choi SH, Liu Y, Skowronska-Krawczyk D, Weinreb RN, Zangwill L, Strack S, Ju WK. Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells. Cell Death Dis 2020; 11:254. [PMID: 32312949 PMCID: PMC7170863 DOI: 10.1038/s41419-020-2456-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/14/2022]
Abstract
Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases in CaN and total Drp1 levels, as well as a decrease in Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.
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Affiliation(s)
- Genea Edwards
- Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
| | - Guy A Perkins
- National Center for Microscopy and Imaging Research and Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
| | - Keun-Young Kim
- National Center for Microscopy and Imaging Research and Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
| | - YeEun Kong
- Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
| | - Yonghoon Lee
- Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
| | - Soo-Ho Choi
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Yujia Liu
- Department of Pharmacology and Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Dorota Skowronska-Krawczyk
- Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
| | - Robert N Weinreb
- Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
| | - Linda Zangwill
- Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
| | - Stefan Strack
- Department of Pharmacology and Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Won-Kyu Ju
- Hamilton Glaucoma Center and Shiley Eye Center, The Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
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49
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Zhu B, Jiang Q, Que G, Dai Z, Wu Y. Role of autophagy and apoptosis in atrophic epithelium in oral submucous fibrosis. J Oral Sci 2020; 62:184-188. [PMID: 32132327 DOI: 10.2334/josnusd.19-0170] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Oral submucous fibrosis (OSF) is a serious, potentially malignant oral disorder. It is histopathologically characterized by chronic inflammation and atrophic epithelium accompanied by the accumulation of collagen fibers in the lamina propria. The molecular mechanisms leading to atrophic epithelium remain poorly understood. Therefore, the present study investigated the role of autophagy and apoptosis in atrophic epithelium in OSF. The expression of Caspase-3 and autophagy-related proteins (LC3 and P62) in OSF epithelial tissues was quantified by immunohistochemistry. The analysis demonstrated that, compared with normal oral mucosal tissues, autophagy and apoptosis increased with the progression of OSF. Flow cytometry and Western blotting showed that arecoline induces apoptosis in human oral keratinocytes (HOKs) in a time-dependent manner in vitro. Arecoline-induced autophagy was confirmed by transmission electron microscopy and Western blotting. When chloroquine was used as an inhibitor of autophagy, the apoptosis rate and Caspase-3 expression decreased compared with the use of arecoline alone. Thus, autophagy and apoptosis may be involved in atrophic epithelium in OSF, and arecoline-induced autophagy promotes apoptosis in HOKs.
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Affiliation(s)
- Bingyu Zhu
- Centre of Stomatology, Xiangya Hospital, Central South University
| | - Qi Jiang
- Centre of Stomatology, Xiangya Hospital, Central South University
| | - Guoying Que
- Department of Stomatology, Guangdong Provincial Stomatological Hospital, Southern Medical University
| | - Zhuo Dai
- Centre of Stomatology, Xiangya Hospital, Central South University
| | - Yingfang Wu
- Centre of Stomatology, Xiangya Hospital, Central South University
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50
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Kumsta C, Chang JT, Lee R, Tan EP, Yang Y, Loureiro R, Choy EH, Lim SHY, Saez I, Springhorn A, Hoppe T, Vilchez D, Hansen M. The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy. Nat Commun 2019; 10:5648. [PMID: 31827090 PMCID: PMC6906454 DOI: 10.1038/s41467-019-13540-4] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 11/13/2019] [Indexed: 02/07/2023] Open
Abstract
Autophagy can degrade cargos with the help of selective autophagy receptors such as p62/SQSTM1, which facilitates the degradation of ubiquitinated cargo. While the process of autophagy has been linked to aging, the impact of selective autophagy in lifespan regulation remains unclear. We have recently shown in Caenorhabditis elegans that transcript levels of sqst-1/p62 increase upon a hormetic heat shock, suggesting a role of SQST-1/p62 in stress response and aging. Here, we find that sqst-1/p62 is required for hormetic benefits of heat shock, including longevity, improved neuronal proteostasis, and autophagy induction. Furthermore, overexpression of SQST-1/p62 is sufficient to induce autophagy in distinct tissues, extend lifespan, and improve the fitness of mutants with defects in proteostasis in an autophagy-dependent manner. Collectively, these findings illustrate that increased expression of a selective autophagy receptor is sufficient to induce autophagy, enhance proteostasis and extend longevity, and demonstrate an important role for sqst-1/p62 in proteotoxic stress responses. While the cellular recycling process autophagy has been linked to aging, the impact of selective autophagy on lifespan remains unclear. Here Kumsta et al. show that the autophagy receptor p62/SQSTM1 is required for hormetic benefits and p62/SQSTM1 overexpression is sufficient to extend C. elegans lifespan and improve proteostasis.
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Affiliation(s)
- Caroline Kumsta
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
| | - Jessica T Chang
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - Reina Lee
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - Ee Phie Tan
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - Yongzhi Yang
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - Rute Loureiro
- Institute for Genetics and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany
| | - Elizabeth H Choy
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - Shaun H Y Lim
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - Isabel Saez
- Institute for Genetics and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany
| | - Alexander Springhorn
- Institute for Genetics and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany
| | - Thorsten Hoppe
- Institute for Genetics and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany
| | - David Vilchez
- Institute for Genetics and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph Stelzmann Strasse 26, 50931, Cologne, Germany
| | - Malene Hansen
- Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
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