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Su K, Tang M, Wu J, Ye N, Jiang X, Zhao M, Zhang R, Cai X, Zhang X, Li N, Peng J, Lin L, Wu W, Ye H. Mechanisms and therapeutic strategies for NLRP3 degradation via post-translational modifications in ubiquitin-proteasome and autophagy lysosomal pathway. Eur J Med Chem 2025; 289:117476. [PMID: 40056798 DOI: 10.1016/j.ejmech.2025.117476] [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: 12/13/2024] [Revised: 02/20/2025] [Accepted: 03/03/2025] [Indexed: 03/10/2025]
Abstract
The NLRP3 inflammasome is crucial for immune responses. However, its overactivation can lead to severe inflammatory diseases, underscoring its importance as a target for therapeutic intervention. Although numerous inhibitors targeting NLRP3 exist, regulating its degradation offers an alternative and promising strategy to suppress its activation. The degradation of NLRP3 is primarily mediated by the proteasomal and autophagic pathways. The review not only elaborates on the traditional concepts of ubiquitination and NLRP3 degradation but also investigates the important roles of indirect regulatory modifications, such as phosphorylation, acetylation, ubiquitin-like modifications, and palmitoylation-key post-translational modifications (PTMs) that influence NLRP3 degradation. Additionally, we also discuss the potential targets that may affect NLRP3 degradation during the proteasomal and autophagic pathways. By unraveling these complex regulatory mechanisms, the review aims to enhance the understanding of NLRP3 regulation and its implications for developing therapeutic strategies to combat inflammatory diseases.
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Affiliation(s)
- Kaiyue Su
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minghai Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Wu
- Key Laboratory of Hydrodynamics (Ministry of Education), School of Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Neng Ye
- Scaled Manufacturing Center of Biological Products, Management Office of National Facility for Translational Medicine, West China Hospital, Sichuan University Chengdu 610041, China
| | - Xueqin Jiang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Min Zhao
- Laboratory of Metabolomics and Drug-induced Liver Injury, Department of Gastroenterology & Hepatology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ruijia Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoying Cai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinlu Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Na Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Peng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lei Lin
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenshuang Wu
- Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Haoyu Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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Lu XF, Zhang HW, Chang X, Guo YZ. F-box protein 22: A prognostic biomarker for colon cancer associated with immune infiltration and chemotherapy resistance. World J Gastrointest Oncol 2025; 17:102913. [DOI: 10.4251/wjgo.v17.i4.102913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/10/2025] [Accepted: 02/21/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Colon cancer represents a significant malignant neoplasm within the digestive system, characterized by a high incidence rate and substantial disease burden. The F-box protein 22 (FBXO22) plays a role in forming a specific type of ubiquitin ligase subunit, which is expressed abnormally in various malignant neoplasms and shows a notable relationship with prognosis in patients with cancer. Nevertheless, the function of FBXO22 in the context of colon cancer remains inadequately elucidated.
AIM To explore the role of FBXO22 in colon cancer by examining FBXO22 expression patterns and analyzing how the protein affects the prognosis in patients who have undergone surgery.
METHODS Samples of cancerous and nearby normal tissues from patients with colon cancer were gathered, along with pertinent clinical data. Expression levels of the FBXO22 gene in both cancerous and paracancerous tissues were assessed through immunohistochemistry. The median H score served as a criterion for categorizing FBXO22 gene expression into high and low levels in cancerous tissues, and the relationship between these expression levels and various pathologic characteristics of patients, such as age, sex, and clinical stage, was analyzed. Colon cancer cell lines HCT116 and DLD-1 were used and divided into three groups: A blank control group, a negative control group, and a si-FBXO22 group. FBXO22 gene mRNA and protein expression were measured 24 hours post-transfection using real-time fluorescence quantitative polymerase chain reaction and western blotting. The proliferation capabilities of the cells in each group were assessed using the Cell Counting Kit-8 assay and 5-ethynyl-2’-deoxyuridine assay, while cellular migration and invasion abilities were evaluated using scratch healing and Transwell assays. Various online platforms, including the Timer Immune Estimation Resource, were used to analyze pan-cancer expression, promoter methylation levels, and mutation frequencies of the FBXO22 gene in colon cancer patients. Additionally, the correlation between FBXO22 gene expression, patient prognosis, immune cell infiltration, and the expression of immune molecules in the colon cancer microenvironment was investigated. The relationship between FBXO22 gene expression and chemotherapy resistance, along with the potential mechanisms of action of the FBXO22 gene, were analyzed using The Cancer Genome Atlas dataset and the Genomics of Drug Sensitivity in Cancer drug training set via R software.
RESULTS Compared with normal colonic tissues, the FBXO22 gene was highly expressed in colon cancer tissues. Post-operative patients with colon cancer elevated FBXO22 reduced survival and exhibited resistance to various chemotherapeutic agents. FBXO22 expression suppresses the infiltration of anti-tumor immune cells. In vitro, FBXO22 knockdown inhibited the proliferation and migration of colon cancer cells.
CONCLUSION The FBXO22 gene is a biomarker of poor prognosis in patients with colon cancer and has potential as a target for immunotherapy and overcoming chemotherapy resistance.
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Affiliation(s)
- Xiao-Fei Lu
- Department of Clinical Medicine, Hebei University of Engineering, Handan 056002, Hebei Province, China
| | - Hong-Wei Zhang
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| | - Xiao Chang
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
| | - Yong-Ze Guo
- Department of Gastroenterology, Affiliated Hospital of Hebei Engineering University, Handan 056002, Hebei Province, China
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3
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Jin SK, Baek KH. Unraveling the role of deubiquitinating enzymes on cisplatin resistance in several cancers. Biochim Biophys Acta Rev Cancer 2025; 1880:189297. [PMID: 40058507 DOI: 10.1016/j.bbcan.2025.189297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/03/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025]
Abstract
The use of platinum-based drugs in cancer treatment is one of the most common methods in chemotherapy. Especially, cisplatin induces cell death by interrupting DNA synthesis by binding to the DNA bases, thereby leading to the apoptosis via multiple pathways. However, the major hurdle in chemotherapy is drug resistance. To overcome drug resistance, the ubiquitin-proteasome system (UPS) has emerged as a potential therapeutic target. The UPS is a pivotal signaling pathway that regulates the majority of cellular proteins by attaching ubiquitin to substrates, leading to proteasomal degradation. Conversely, deubiquitinating enzymes (DUBs) remove tagged ubiquitin from the substrate and inhibit degradation, thereby maintaining proteostasis. Recently, studies have been conducted to identify the substrates of DUBs and investigated the cellular mechanisms, and now the development of therapeutics using DUB inhibitors is in clinical trials. However, the mechanism of the DUB response to cisplatin remains still unclear. In this review, we summarize the research reported on the function of DUBs responding to cisplatin.
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Affiliation(s)
- Sun-Kyu Jin
- Department of Biomedical Science, CHA University, Gyeonggi-Do 13488, Republic of Korea
| | - Kwang-Hyun Baek
- Department of Biomedical Science, CHA University, Gyeonggi-Do 13488, Republic of Korea.
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4
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Coughlin DJ, Dutterer MD, LaMonica ZD, Peyton EM, Kwon ES, Hittle KA. Muscle and Metabolic Genes Are Differentially Expressed During Thermal Acclimation by the Brook Trout Myotome. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2025; 343:416-426. [PMID: 39817681 DOI: 10.1002/jez.2901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 12/11/2024] [Accepted: 01/03/2025] [Indexed: 01/18/2025]
Abstract
Cold-water fishes, such as Brook trout (Salvelinus fontinalis), are being challenged by the consequences of climate change. The ability of these fish to acclimate to warmer environmental conditions is vital to their survival. Acclimation to warmer water may allow brook trout to reduce the metabolic costs of higher temperatures. Previous work has shown that brook trout display a significant thermal acclimation response in their myotomal muscle, with slower contractile properties observed in warm acclimated fish. In this study, gene expression was examined in hatchery brook trout acclimated to a range in temperatures (4, 10 or 20°C). Brook trout displayed variations in gene expression in their myotomal muscle in accordance with acclimation temperature. Genes important for muscle function, cellular metabolism, protein degradation, and stress response showed variation to both warm (20°C) and cold (4°C) acclimation. The warm acclimated fish also showed decreased expression of genes associated with aerobic metabolism and increased expression of genes for heat shock proteins, while the cold acclimated fish showed increased expression of genes associated with lipid metabolism and protein turnover. α-tubulin displayed a close association with thermal acclimation, increasing in expression with acclimation temperature. The patterns of muscle gene expression were the opposite of what was expected. Although warm acclimated fish have previously been shown to display slow muscle contractile properties, this study found that warm acclimation is associated with increased expression of genes for kinetically faster isoforms of important muscle proteins. Collectively, the results demonstrate a robust response to elevated temperature in the hatchery fish greater than 10,000 genes showing differential expression with temperature. These results provide a roadmap for the analysis of the acclimation response of native populations of brook trout encountering climate change.
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Affiliation(s)
- David J Coughlin
- Department of Biology, Widener University, Chester, Pennsylvania, USA
| | | | | | - Evelyn M Peyton
- Department of Biology, Widener University, Chester, Pennsylvania, USA
| | - Elizabeth S Kwon
- Department of Biology, Widener University, Chester, Pennsylvania, USA
| | - Kathleen A Hittle
- Department of Biology, Widener University, Chester, Pennsylvania, USA
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5
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Li Y, Ma C, Sheng Y, Huang S, Sun H, Ti Y, Wang Z, Wang F, Chen F, Li C, Guo H, Tang M, Song F, Wang H, Zhong M. TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease. J Clin Invest 2025; 135:e175972. [PMID: 39932798 PMCID: PMC11957692 DOI: 10.1172/jci175972] [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: 10/03/2023] [Accepted: 02/04/2025] [Indexed: 02/13/2025] Open
Abstract
The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in ER stress in chronic kidney disease (CKD). Controlling ER stress through genetic intervention is a promising approach for treating vascular calcification. In this study, we demonstrated a positive correlation between ER stress-induced tribble homolog 3 (TRIB3) expression and progression of vascular calcification in human and rodent CKD. Increased TRIB3 expression promoted vascular smooth muscle cell (VSMC) calcification by interacting with the C2 domain of the E3 ubiquitin-protein ligase Smurf1, facilitating its K48-related self-ubiquitination at Lys381 and Lys383 and subsequent dissociation from the plasma membrane and nuclei. This degeneration of Smurf1 accelerated the stabilization of the osteogenic transcription factors RUNX family transcription factor 2 (Runx2) and SMAD family member 1 (Smad1). C/EBP homologous protein and activating transcription factor 4 are upstream transcription factors of TRIB3 in an osteogenic environment. Genetic KO of TRIB3 or rescue of Smurf1 ameliorated VSMC and vascular calcification by stabilizing Smurf1 and enhancing the degradation of Runx2 and Smad1. Our findings shed light on the vital role of TRIB3 as a scaffold in ER stress and vascular calcification and offer a potential therapeutic option for CKD.
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Affiliation(s)
- Yihui Li
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
- Department of Critical Care Medicine, Qilu Hospital, Innovation Research Center for Sepsis and Multiple Organ Injury, Shandong University, Jinan, China
| | - Chang Ma
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yanan Sheng
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Shanying Huang
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Huaibing Sun
- Department of Organ Transplantation, Qilu Hospital, and
| | - Yun Ti
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Zhihao Wang
- Department of Geriatric Medicine, Qilu Hospital, Shandong University, Jinan, China
| | - Feng Wang
- Department of Critical Care Medicine, Shandong Provincial Hospital, Jinan, Shandong, China
| | - Fangfang Chen
- Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Chen Li
- Department of Critical Care Medicine, Qilu Hospital, Innovation Research Center for Sepsis and Multiple Organ Injury, Shandong University, Jinan, China
| | - Haipeng Guo
- Department of Critical Care Medicine, Qilu Hospital, Innovation Research Center for Sepsis and Multiple Organ Injury, Shandong University, Jinan, China
| | - Mengxiong Tang
- Department of Emergency, Qilu Hospital, Shandong University, Jinan, China
| | - Fangqiang Song
- Department of Critical Care Medicine, Affiliated Tengzhou Hospital of Xuzhou Medical University/Tengzhou Central People’s Hospital, Shandong, China
| | - Hao Wang
- Department of Critical Care Medicine, Qilu Hospital, Innovation Research Center for Sepsis and Multiple Organ Injury, Shandong University, Jinan, China
| | - Ming Zhong
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
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Madhukar G, Haque MA, Khan S, Kim JJ, Danishuddin. E3 ubiquitin ligases and their therapeutic potential in disease Management. Biochem Pharmacol 2025; 236:116875. [PMID: 40120724 DOI: 10.1016/j.bcp.2025.116875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 02/05/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
Ubiquitination is a vital post-translational modification that regulates protein stability and various cellular processes through the addition of ubiquitin molecules. Central to this process are E3 ubiquitin ligases, which determine the specificity of ubiquitination by coordinating the attachment of ubiquitin to target proteins, influencing their degradation, localization, and activity. E3 ubiquitin ligases are involved in numerous cellular pathways, including DNA repair, cell proliferation, and immune responses. Dysregulation of E3 ubiquitin ligases is often associated with cancer, contributing to tumor progression and resistance to therapies. The development of targeted protein degraders, such as proteolysis-targeting chimeras (PROTACs), represents a significant advancement in drug discovery, leveraging the specificity of E3 ubiquitin ligases to selectively eliminate pathogenic proteins. However, challenges remain in translating this knowledge into effective therapies, including issues related to tissue-specific targeting and off-target effects. The limitations also include a limited understanding of ligase-substrate interactions that includes both the identification of novel E3 ligases and their substrates, as well as understanding the dynamic, context-dependent nature of these interactions, which can vary across tissue types or disease states This review emphasizes the therapeutic potential of E3 ubiquitin ligases, exploring their diverse roles in disease, their contribution to targeted degradation strategies while highlighting the need for further research to overcome current limitations and enhance therapeutic efficacy.
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Affiliation(s)
- Geet Madhukar
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH 03824, USA
| | - Md Azizul Haque
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
| | - Shawez Khan
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730 Herlev, Denmark
| | - Jong-Joo Kim
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
| | - Danishuddin
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
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7
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Durán-Cristiano SC, de Diego-García L, Martín-Gil A, Carracedo G. The Role of the Ubiquitin System in Eye Diseases. Life (Basel) 2025; 15:504. [PMID: 40141848 PMCID: PMC11943997 DOI: 10.3390/life15030504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/11/2025] [Accepted: 03/19/2025] [Indexed: 03/28/2025] Open
Abstract
The ubiquitin-proteasome system (UPS) is a fundamental process that regulates various biological functions, including immune response, cell cycle, oxidative stress, migration, and cellular proliferation. This system is responsible for the degradation of proteins, while proteasomes play a significant role in mechanisms involved in health and human diseases. The participation of the UPS in immune response is particularly relevant, leading to the involvement of immunoproteasomes. This specialized proteasome is involved in the processing and presentation of antigenic peptides, making it crucial for proper immune function. Moreover, the impact of the UPS is considered essential in understanding several diseases, such as neurodegenerative disorders, infections, and vascular diseases. The dysregulation of the UPS may contribute to the pathogenesis of these conditions, highlighting its importance as a potential therapeutic target. Interestingly, the UPS is also related to ocular structures, playing a role in visual perception and ocular homeostasis. This involvement in the regulation of various ocular processes suggests its potential impact on both anterior and posterior eye pathologies. This review aims to discuss the general considerations of the UPS and provide information about its participation in anterior and posterior eye pathologies. By understanding its role in ocular health and disease, researchers and clinicians may explore novel therapeutic strategies targeting the UPS for the treatment of various eye conditions. In conclusion, the UPS is a crucial player in biological processes, with far-reaching implications in health and disease, including the anterior and posterior segments of the eye. Further research in this field may lead to the development of innovative therapies and a better understanding of the complex mechanisms underlying various eye disorders.
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Affiliation(s)
| | - Laura de Diego-García
- Department of Biochemistry and Molecular Biology, Faculty of Optics and Optometry, Universidad Complutense de Madrid, 28037 Madrid, Spain
| | - Alba Martín-Gil
- Department of Optometry and Vision, Faculty of Optics and Optometry, Universidad Complutense de Madrid, 28037 Madrid, Spain; (A.M.-G.); (G.C.)
| | - Gonzalo Carracedo
- Department of Optometry and Vision, Faculty of Optics and Optometry, Universidad Complutense de Madrid, 28037 Madrid, Spain; (A.M.-G.); (G.C.)
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8
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Xu H, Zheng S, Zhang Q, Xu Y, Zhang H, Hu T, Zhang X, E J, Li X, Wang R, Liu H, Xie R. CUL1-neddylation contributes to K29-linked ubiquitination on p27 for autophagic degradation in sorafenib-resistant liver cancer. Cell Biol Toxicol 2025; 41:61. [PMID: 40111576 PMCID: PMC11926008 DOI: 10.1007/s10565-025-10008-8] [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: 11/01/2024] [Accepted: 03/10/2025] [Indexed: 03/22/2025]
Abstract
Sorafenib has demonstrated great efficacy in liver cancer, however, its application as first-line treatment has been hampered due to the emerging drug resistance. This study is aimed to investigate the mechanism underlying acquired sorafenib resistance in liver cancer. Based on GSE109211 and TCGA datasets, bioinformatics analysis was conducted to find the potential genes implicated in the sorafenib resistance in liver cancer. mCherry-/eGFP-LC3B dual-fluorescent system was used to assess autophagic state. Wild and mutant types of HA-labeled ubiquitin (K27, K29, K33, K48, K63, K29R and K48R) were used to identify the type of polyubiquitin chains added to p27 by CUL1. Herein, we identified that F-box protein (SCF) ubiquitin ligase complexes (CUL1 and SKP2) and NEDD8 were highly expressed in sorafenib-resistant tissues using both the public data and clinical samples. NEDD8-mediated CUL1 neddylation enhanced SCF ubiquitin ligase complex to target p27 and subsequently linked K29-linked polyubiquitin chains to p27. Furthermore, NBR1 facilitated the degradation of ubiquitinated p27 protein by enhancing autophagy flux. Knocking down of CUL1 could prevent ubiquitination- and autophagy-mediated p27 protein degradation. The resistance to sorafenib was suppressed with CUL1 knockdown both in vitro and in vivo. In conclusion, our findings indicated that blocking neddylation or autophagy can restore drug sensitivity, thus providing a potential strategy for overcoming sorafenib resistance in the future.
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Affiliation(s)
- Haitao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Shaoyue Zheng
- Department of Endoscope, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Qiuqi Zhang
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Ying Xu
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Hanbo Zhang
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Tianming Hu
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Xiaoling Zhang
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiaoting E
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Xuedong Li
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Ruitao Wang
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
| | - Hongyan Liu
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
| | - Rui Xie
- Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
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9
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Sahu M, Jain U. Activation, interaction and intimation of Nrf2 pathway and their mutational studies causing Nrf2 associated cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167764. [PMID: 40088576 DOI: 10.1016/j.bbadis.2025.167764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/15/2025] [Accepted: 02/25/2025] [Indexed: 03/17/2025]
Abstract
Responses against infection trigger several signaling pathways that lead to the production of cytokines, these cytokines release ROS and RNS, damaging DNA and proteins turn into various diseases including cancer. To combat these harmful cytokines, the Nrf2 pathway is activated. The gene NFE2L2 encodes Nrf2, which is divided into seven conserved domains (Neh1-7). The DLG and ETGE motifs, conserved sequences of amino acid in the Neh2 domain of Nrf2, bind to the BTB domain of Keap1. BTB domain promotes Keap1's homodimerization resulting in Cul3 recruitment providing scaffold formation to E2 ubiquitin ligase to form ubiquitin complex. Under normal conditions, this complex regularly degrades Nrf2. However, once the cell is exposed to oxidative stress by ROS interaction with Keap1 resulting in conformational changes that stabilize the Nrf2. Nrf2 further concentrates on the nucleus where it binds with the transcriptional factor to perform the desired genes transcription for synthesizing SOD, GSH, CAT, and various other proteins which reduce the ROS levels preventing certain diseases. To prevent cells from oxidative stress, molecular hydrogen activates the Nrf2 pathway. To activate the Nrf2 pathway, molecular hydrogen oxidizes the iron porphyrin which acts as an electrophile and interacts with Keap1's cysteine residue.
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Affiliation(s)
- Mridul Sahu
- School of Health Sciences and Technology (SoHST), UPES, Bidholi, Dehradun - 248007, India
| | - Utkarsh Jain
- School of Health Sciences and Technology (SoHST), UPES, Bidholi, Dehradun - 248007, India.
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10
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Zou XJ, Zhang YH, Zhang C, Yuan XF, Yun MJ, Xie LJ, Liu XQ, Kang WF, Chen W, Liu YX, Wang AY, Lu ZJ, Yu HZ. Diaphorina citri E3 ubiquitin ligase RNF115 inhibits CLas bacterial proliferation by targeting to the host histone H1. INSECT SCIENCE 2025. [PMID: 40079889 DOI: 10.1111/1744-7917.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/15/2025] [Accepted: 01/28/2025] [Indexed: 03/15/2025]
Abstract
The Asian citrus psyllid (ACP), Diaphorina citri, serves as the primary vector for Candidatus Liberibacter asiaticus (CLas), the pathogen responsible for citrus Huanglongbing (HLB). D. citri modulates the expression of its key proteins in response to CLas infection. Previous research has revealed that CLas infection significantly alters the expression levels of E3 ubiquitin ligases in D. citri; however, the specific functions of these E3 ligases remain largely uncharacterized. In this study, a total of 11 E3 ubiquitin ligases were identified from the proteomics database of D. citri, among which E3 ubiquitin ligase RNF115 was significantly upregulated following CLas infection. RING finger protein 115 (RNF115) consists of 156 amino acids and contains a RING finger domain at its N-terminus. Silencing RNF115 via RNA interference (RNAi) and injecting the inhibitor disulfiram, which targets RNF115, significantly increased CLas bacterial content in D. citri. In contrast, injection of recombinant RNF115 protein markedly inhibited CLas bacterial proliferation. Furthermore, interaction between RNF115 and D. citri histone H1 was confirmed using yeast 2-hybrid assay, pull-down experiments and molecular docking analysis. Knockdown of histone H1 via RNAi significantly reduced CLas bacterial content, whereas injection of recombinant histone H1 protein led to an increase in CLas content within D. citri. These findings suggest that CLas infection may induce an upregulation of RNF115 expression in D. citri, leading to subsequent interactions with histone H1 that facilitate the ubiquitination of histone H1, ultimately resulting in reduced expression levels and inhibiting CLas proliferation within D. citri.
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Affiliation(s)
- Xiao-Jin Zou
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Yi-Hong Zhang
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Can Zhang
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Xiao-Fang Yuan
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Meng-Jun Yun
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Lian-Jie Xie
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Xiao-Qiang Liu
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
- Jiangxi Provincial Key Laboratory of Pest and Disease Control of Featured Horticultural Plants, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Wen-Feng Kang
- Xinfeng County Agriculture and Rural Bureau, Ganzhou, Jiangxi Province, China
| | - Wei Chen
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
- Jiangxi Provincial Key Laboratory of Pest and Disease Control of Featured Horticultural Plants, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Ying-Xue Liu
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
- Jiangxi Provincial Key Laboratory of Pest and Disease Control of Featured Horticultural Plants, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Ai-Yun Wang
- Fruit Bureau of Xinfeng County, Ganzhou, Jiangxi Province, China
| | - Zhan-Jun Lu
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
- Jiangxi Provincial Key Laboratory of Pest and Disease Control of Featured Horticultural Plants, Gannan Normal University, Ganzhou, Jiangxi Province, China
| | - Hai-Zhong Yu
- School of Life Sciences, Gannan Normal University, Ganzhou, Jiangxi Province, China
- Jiangxi Provincial Key Laboratory of Pest and Disease Control of Featured Horticultural Plants, Gannan Normal University, Ganzhou, Jiangxi Province, China
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11
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Tylicka M, Matuszczak E, Kamińska J, Modzelewska B, Koper-Lenkiewicz OM. Proteasomes and Ubiquitin C-Terminal Hydrolase L1 as Biomarkers of Tissue Damage and Inflammatory Response to Different Types of Injury-A Short Review. Life (Basel) 2025; 15:413. [PMID: 40141757 PMCID: PMC11944130 DOI: 10.3390/life15030413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 02/21/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025] Open
Abstract
The proteasomal system of protein degradation is crucial for various cellular processes, including transduction of signals and differentiation of cells. Proteasome activity rises after various traumatic stressors such as hyperoxia, radiation, or oxidative damage. Removal of damaged proteins is essential to provide the necessary conditions for cell repair. Several studies report the activation of the proteasomal degradation system after thermal injury, CNS injury, abdominal trauma, ischemia-reperfusion injury, and possible clinical implications of the use of proteasome inhibitors. It is important to highlight the distinct and crucial roles of UCHL1, 26S, and 20S proteasome subunits as biomarkers. UCHL1 appears to be particularly relevant for identifying brain and neuronal damage and in advancing the diagnosis and prognosis of traumatic brain injury (TBI) and other neurological conditions. Meanwhile, the 26S and 20S proteasomes may serve as markers for peripheral tissue damage. This differentiation enhances our understanding and ability to target specific types of tissue damage in clinical settings.
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Affiliation(s)
- Marzena Tylicka
- Department of Biophysics, Medical University of Bialystok, Mickiewicza 2a, 15-222 Bialystok, Poland;
| | - Ewa Matuszczak
- Department of Pediatric Surgery, Medical University of Bialystok, Waszyngtona 17, 15-274 Bialystok, Poland;
| | - Joanna Kamińska
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Waszyngtona 15A, 15-269 Bialystok, Poland; (J.K.); (O.M.K.-L.)
| | - Beata Modzelewska
- Department of Biophysics, Medical University of Bialystok, Mickiewicza 2a, 15-222 Bialystok, Poland;
| | - Olga Martyna Koper-Lenkiewicz
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Waszyngtona 15A, 15-269 Bialystok, Poland; (J.K.); (O.M.K.-L.)
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12
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Han L, Begum Yagci Z, Keung AJ. A high sensitivity assay of UBE3A ubiquitin ligase activity. Methods 2025; 235:92-99. [PMID: 39933617 DOI: 10.1016/j.ymeth.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/29/2025] [Accepted: 02/07/2025] [Indexed: 02/13/2025] Open
Abstract
UBE3A is an E3 ubiquitin ligase associated with several neurodevelopmental disorders. The development of several preclinical therapeutic approaches involving UBE3A, such as gene therapy, enzyme replacement therapy, and epigenetic reactivation, require the detection of its ubiquitin ligase activity. Prior commercial assays leveraged Western Blotting to detect shifts in substrate size due to ubiquitination, but these suffered from long assay times and have also been discontinued. Here we develop a new assay that quantifies UBE3A activity. It measures the fluorescence intensity of ubiquitinated p53 substrates with a microplate reader, eliminating the need for Western Blot antibodies and instruments, and enables detection in just 1 h. The assay is fast, cost-effective, low noise, and uses components with long shelf lives. Importantly, it is also highly sensitive, detecting UBE3A levels as low as 1 nM, similar to that observed in human and mouse cerebrospinal fluid. It also differentiates the activity of wild-type UBE3A and catalytic mutants. We also design a p53 substrate with a triple-epitope tag HIS-HA-CMYC on the N terminus, which allows for versatile detection of UBE3A activity from diverse natural and engineered sources. This new assay provides a timely solution for growing needs in preclinical validation, quality control, endpoint measurements for clinical trials, and downstream manufacturing testing and validation.
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Affiliation(s)
- Linna Han
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, Raleigh, NC 27695-7905, USA.
| | - Z Begum Yagci
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, Raleigh, NC 27695-7905, USA
| | - Albert J Keung
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, Raleigh, NC 27695-7905, USA.
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13
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Meli R, Aksoy O, Vallet S, Slade D, Podar K. Can we develop effective direct or indirect inhibitors of transcription factors? On the clinical evolution of protein degraders for multiple myeloma therapy. Expert Opin Ther Targets 2025; 29:101-115. [PMID: 40122131 DOI: 10.1080/14728222.2025.2482557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/26/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Transcription factors (TFs) are master regulators of cellular function and orchestrate diverse signaling pathways and processes. Acting as convergence points of signaling pathways, they integrate extracellular stimuli with intracellular responses to regulate cell functions. Dysregulation of TFs drives tumorigenesis including proliferation, drug resistance, and immune evasion of multiple myeloma (MM), the second most-common hematologic malignancy. AREAS COVERED The discovery that IMiDs are molecular glue degraders, which reprogram the E3-ligase cereblon (CRBN) to ubiquitinate and degrade IKZF1 and IKZF3, two otherwise un-druggable crucial TFs in MM, gave rise to the widespread interest in proximity-induced protein-degradation as an exciting novel therapeutic strategy. This review summarizes our up-to-date knowledge on the pre/clinical development of IMiD-related, more potent CRBN E3-Ligase Modulatory Drugs (CELMoDs), directed PROteolysis TArgeting Chimeras (PROTACs) and degronomids as well as on promising future avenues in the field of targeted protein-degradation (TPD). EXPERT OPINION TPD is an emerging field to treat cancer, including MM. CELMoDs are already reshaping the treatment landscape of MM. Preclinical data on PROTACs are promising. Nevertheless, a deeper understanding of TF biology as well as further advancements in screening methodologies and chemoproteomics are crucial to further spur the transformative potential of targeted TF degradation in MM.
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Affiliation(s)
- Rajeshwari Meli
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
| | - Osman Aksoy
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
| | - Sonia Vallet
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
- Division of Internal Medicine, University Hospital Krems, Krems an der Donau, Austria
| | - Dea Slade
- MedAustron Ion Therapy Center, Wiener Neustadt, Austria
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria
- Center for Medical Biochemistry, Medical University of Vienna, Vienna, Austria
| | - Klaus Podar
- Division of Molecular Oncology and Hematology, Department of Basic and Translational Oncology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
- Division of Internal Medicine, University Hospital Krems, Krems an der Donau, Austria
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14
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Sias F, Zoroddu S, Migheli R, Bagella L. Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target. Int J Mol Sci 2025; 26:1973. [PMID: 40076599 PMCID: PMC11900228 DOI: 10.3390/ijms26051973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 02/14/2025] [Accepted: 02/17/2025] [Indexed: 03/14/2025] Open
Abstract
MYC plays a pivotal role in the biology of various sarcoma subtypes, acting as a key regulator of tumor growth, proliferation, and metabolic reprogramming. This oncogene is frequently dysregulated across different sarcomas, where its expression is closely intertwined with the molecular features unique to each subtype. MYC interacts with critical pathways such as cell cycle regulation, apoptosis, and angiogenesis, amplifying tumor aggressiveness and resistance to standard therapies. Furthermore, MYC influences the tumor microenvironment by modulating cell-extracellular matrix interactions and immune evasion mechanisms, further complicating therapeutic management. Despite its well-established centrality in sarcoma pathogenesis, targeting MYC directly remains challenging due to its "undruggable" protein structure. However, emerging therapeutic strategies, including indirect MYC inhibition via epigenetic modulators, transcriptional machinery disruptors, and metabolic pathway inhibitors, offer new hope for sarcoma treatment. This review underscores the importance of understanding the intricate roles of MYC across sarcoma subtypes to guide the development of effective targeted therapies. Given MYC's central role in tumorigenesis and progression, innovative approaches aiming at MYC inhibition could transform the therapeutic landscape for sarcoma patients, providing a much-needed avenue to overcome therapeutic resistance and improve clinical outcomes.
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Affiliation(s)
- Fabio Sias
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100 Sassari, Italy; (F.S.); (S.Z.)
| | - Stefano Zoroddu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100 Sassari, Italy; (F.S.); (S.Z.)
| | - Rossana Migheli
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, 07100 Sassari, Italy;
| | - Luigi Bagella
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100 Sassari, Italy; (F.S.); (S.Z.)
- Sbarro Institute for Cancer Research and Molecular Medicine, Centre for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
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15
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Zhou L, Li L, Yang J, Mansuer M, Deng X, Wang Y, Ren H, Cui D, Jiang Y, Gao L. TNFAIP3 affects ferroptosis after traumatic brain injury by affecting the deubiquitination and ubiquitination pathways of the HMOX1 protein and ACSL3. Free Radic Biol Med 2025; 228:221-239. [PMID: 39743027 DOI: 10.1016/j.freeradbiomed.2024.12.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/04/2025]
Abstract
The occurrence and progression of traumatic brain injury involve a complex process. The pathophysiological mechanisms triggered by neuronal damage include various forms of programmed cell death, including ferroptosis. We observed upregulation of TNFAIP3 in mice after traumatic brain injury. Overexpression of TNFAIP3 inhibits HT-22 proliferation and cell viability through ferroptosis. Mechanistically, TNFAIP3 interacts with the HMOX1 protein and promotes its stability through the deubiquitination pathway. Additionally, TNFAIP3 can enhance lipoperoxidation, mitochondrial damage, and neuronal cell death by promoting ACSL3 degradation via NEDD4-mediated ubiquitination. Mice injected with AAV-shTNFAIP3 exhibited reduced neuronal degeneration and improved motor and cognitive function following cortical impact injury. In conclusion, our findings demonstrate that TNFAIP3 deficiency inhibits neuronal cell ferroptosis and ameliorates cognitive impairment caused by traumatic brain injury and demonstrate its potential applicability in the treatment of traumatic brain injury.
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Affiliation(s)
- Lin Zhou
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Lei Li
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jinghao Yang
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Maierdan Mansuer
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Xianyu Deng
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yida Wang
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Hui Ren
- Department of Central Laboratory, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200435, China
| | - Daming Cui
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Yang Jiang
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Liang Gao
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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16
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Wong PF, Kamarul T. Targeting Ubiquitin-Proteasome system (UPS) in treating osteoarthritis. Eur J Pharmacol 2025; 989:177237. [PMID: 39732357 DOI: 10.1016/j.ejphar.2024.177237] [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: 08/03/2024] [Revised: 11/21/2024] [Accepted: 12/23/2024] [Indexed: 12/30/2024]
Abstract
Despite osteoarthritis (OA) being recognised for over a century as a debilitating disease that affects millions, there are huge gaps in our understanding of the underlying pathophysiology that drives this disease. Present day studies that focussed on ubiquitination (Ub) and ubiquitylation-like (Ubl) modification related mechanisms have brought light into the possibility of attenuating OA development by targeting these specific proteins in chondrocytes. In the present review, we discuss recent advances in studies involving Ub ligases and deubiquitinating enzymes (DUBs) which are of importance in the development of OA, and may offer potential therapeutic strategies for OA. Such targets may involve attenuating proteases such as matrix metalloproteinases (MMP) 1, 8, 13, 4 and several A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) that are well known for their roles in cartilage breakdown. Ligases such as ubiquitin-conjugating enzymes (E2) and ubiquitin-ligating enzymes (E3) that are involved in extracellular matrix (ECM) degradation in OA and of their pathogenesis would be discussed. In addition to catabolic and degenerative downstream effects of Ub and DUBs in OA, inflammatory mechanisms most notably involving nuclear factor-kappa B (NF-κB) signalling pathways regulated through Ub and using various targeting molecules would also be highlighted. Challenges, gaps and insights from clinical trials will provide valuable guidance for future investigations on targeting ubiquitin-proteosome system (UPS) as a therapeutic option for OA.
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Affiliation(s)
- Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, 50603 Kuala Lumpur, Malaysia.
| | - Tunku Kamarul
- National Orthopaedic Centre of Excellence in Research and Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia
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17
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Wei CH, Weng CW, Wu CY, Chen HY, Chang YH, Chang GC, Chen JJW. E3 ligase TRIM8 suppresses lung cancer metastasis by targeting MYOF degradation through K48-linked polyubiquitination. Cell Death Dis 2025; 16:88. [PMID: 39934162 DOI: 10.1038/s41419-025-07421-6] [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: 05/10/2024] [Revised: 01/14/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
Ubiquitination is a posttranslational modification that regulates tumour progression-associated proteins through the ubiquitin‒proteasome system, making E3 ligases potential antitumour targets. Here, we report that TRIM8, a member of the TRIM family and an E3 ligase, can act as a tumour suppressor in non-small cell lung cancer (NSCLC). Both gain- and loss-of-function experiments revealed that TRIM8 inhibits the proliferation, colony formation, migration and invasion of NSCLC cells. Experiments with a xenograft model showed that TRIM8 expression suppresses tumour metastasis in vivo. Moreover, low expression of TRIM8 was associated with poor overall survival in both the Taiwanese and GEO lung cancer cohorts. TRIM8 overexpression in lung cancer cells reduced MYOF expression, and restoring MYOF rescued cell migration in TRIM8-overexpressing cells. TRIM8 targeted MYOF for K48-linked ubiquitination, facilitating proteasome-mediated degradation and subsequently suppressing the extracellular secretion of MMPs. Our results provide new insights into the contribution of TRIM8 to lung cancer progression, suggesting that TRIM8 is a new biomarker and a novel therapeutic target for lung cancer.
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Affiliation(s)
- Chi-Hsuan Wei
- Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Chia-Wei Weng
- Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- School of Medicine and Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chih-Ying Wu
- Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hsuan-Yu Chen
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Ya-Hsuan Chang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Gee-Chen Chang
- Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- School of Medicine and Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Jeremy J W Chen
- Graduate Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
- Graduate Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.
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18
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Bochalis E, Patsakis M, Chantzi N, Mouratidis I, Chartoumpekis D, Georgakopoulos-Soares I. Unraveling diversity by isolating peptide sequences specific to distinct taxonomic groups. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.05.636664. [PMID: 39975352 PMCID: PMC11839104 DOI: 10.1101/2025.02.05.636664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
The identification of succinct, universal fingerprints that enable the characterization of individual taxonomies can reveal insights into trait development and can have widespread applications in pathogen diagnostics, human healthcare, ecology and the characterization of biomes. Here, we investigated the existence of peptide k-mer sequences that are exclusively present in a specific taxonomy and absent in every other taxonomic level, termed taxonomic quasi-primes. By analyzing proteomes across 24,073 species, we identified quasi-prime peptides specific to superkingdoms, kingdoms, and phyla, uncovering their taxonomic distributions and functional relevance. These peptides exhibit remarkable sequence uniqueness at six- and seven-amino-acid lengths, offering insights into evolutionary divergence and lineage-specific adaptations. Moreover, we show that human quasi-prime loci are more prone to harboring pathogenic variants, underscoring their functional significance. This study introduces taxonomic quasi-primes and offers insights into their contributions to proteomic diversity, evolutionary pathways, and functional adaptations across the tree of life, while emphasizing their potential impact on human health and disease.
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Affiliation(s)
- Eleftherios Bochalis
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Department of Internal Medicine, Division of Endocrinology, Medical School, University of Patras, Patras, Greece
| | - Michail Patsakis
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Nikol Chantzi
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Ioannis Mouratidis
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Dionysios Chartoumpekis
- Department of Internal Medicine, Division of Endocrinology, Medical School, University of Patras, Patras, Greece
| | - Ilias Georgakopoulos-Soares
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
- Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA, USA
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19
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Wang HJ, Dong LF, Ding LL, Miao XY, Zhang YW, Zhao LP, Yu LH, Guan ZR, Jiang YP, Tang XQ, Yan YX, Lou JS. TFEB promotes Ginkgetin-induced ferroptosis via TRIM25 mediated GPX4 lysosomal degradation in EGFR wide-type lung adenocarcinoma. Theranostics 2025; 15:2991-3012. [PMID: 40083935 PMCID: PMC11898290 DOI: 10.7150/thno.106469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/27/2025] [Indexed: 03/16/2025] Open
Abstract
Rationale: TFEB activation is associated with prolonged survival in LUAD patients, suggesting potential benefits of TFEB agonists in LUAD treatment. In this study, we identify ginkgetin (GK), derived from Ginkgo folium, as a natural TFEB agonist, which has demonstrated promising anticancer effects in our previous research. TFEB activation has been shown to promote GPX4 degradation, inducing ferroptosis; however, the specific E3 ligases, deubiquitinating enzymes (DUBs), and types of polyubiquitination chains involved remain unclear. The unique mechanisms associated with natural compounds like GK may help elucidate the underlying biological processes. Here, we describe a novel biological event involved in the lysosomal degradation of GPX4 induced by TFEB activation through the utilization of GK. Methods: TFEB activation was induced with GK, and TFEB knockout cells were generated using CRISPR-Cas9. The activity of TFEB and its relationship with ferroptosis were assessed by immunoprecipitation, labile iron pool and lysosomal activity assays. The types of polyubiquitination chains, E3 ligases, and DUBs involved in GPX4 degradation were analyzed using LC-MS, immunoprecipitation, and immunofluorescence. These findings were further validated in an orthotopic xenograft SCID mouse model. Results: GK binds to and activates TFEB, leading to TFEB-mediated lysosomal activation and GPX4 degradation, which induces ferroptosis in LUAD cells. These effects were impaired in TFEB knockout cells. Mechanistically, K48-linked polyubiquitination of GPX4 was required for GK induced GPX4 lysosomal translocation. TFEB knockout reduced both K48-linked ubiquitination and lysosomal translocation of GPX4. Additionally, GK promotes the binding of TFEB and TRIM25. TRIM25 and USP5 were found to competitively bind to GPX4, with TFEB activation favoring TRIM25 binding to GPX4 and reducing the interaction of USP5 and GPX4. These findings were confirmed in a xenograft SCID mouse model using TFEB knockout LUAD cells. Conclusion: This study identifies, for the first time, GK as a promising TFEB agonist for LUAD treatment. TFEB activation promotes TRIM25-mediated K48-linked polyubiquitination and lysosomal degradation of GPX4, driving ferroptosis. This ferroptosis-driven mechanism offers a novel strategy to enhance ferroptosis-based anti-LUAD therapies.
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Affiliation(s)
- Hao-Jie Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ling-feng Dong
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Li-Li Ding
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiu-Yuan Miao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Yu-Wen Zhang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Li-Ping Zhao
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Li-Hua Yu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Zhen-Rong Guan
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Ya-Ping Jiang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Xiao-Qi Tang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Ya-Xin Yan
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Jian-Shu Lou
- School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
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20
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Han J, Shin YH, Kim E, Park HM, Kim JY. Proteomic Characterization of NEDD4 Unveils Its Potential Novel Downstream Effectors in Gastric Cancer. J Proteome Res 2025; 24:891-902. [PMID: 39874481 DOI: 10.1021/acs.jproteome.4c01109] [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: 01/30/2025]
Abstract
The E3 ubiquitin ligase neural precursor cell-expressed developmentally down-regulated 4 (NEDD4) is involved in various cancer signaling pathways, including PTEN/AKT. However, its role in promoting gastric cancer (GC) progression is unclear. This study was conducted to elucidate the role of NEDD4 in GC progression. We found that the inhibition of NEDD4 expression significantly reduced the migratory and proliferative abilities of GC cells, with minimal impact on the PTEN expression or p-AKT activation, suggesting that NEDD4 may exert its GC-promoting effects through alternative pathways. To gain novel insights into the role of NEDD4 in GC, we performed a comprehensive proteomic analysis to search for proteins with altered expression levels following NEDD4 gene knockdown, identifying a total of 3916 proteins. Pathway analysis of differentially expressed proteins (DEPs) indicated the potential involvement of NEDD4 in cancer-related metabolic pathways. Furthermore, the protein-protein interaction network of the DEPs revealed enriched core modules, highlighting key cellular processes and signaling pathways regulated by NEDD4 in GC. Additionally, we identified proteins whose expression was altered by NEDD4 inhibition, some of which were associated with poor prognosis in GC. These findings suggest that these proteins may act as downstream effectors that contribute to NEDD4-mediated GC progression.
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Affiliation(s)
- Jisoo Han
- Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon 34134, Republic of Korea
| | - Yoon-Hee Shin
- Advanced Analysis and Data Center, Korea Institute of Science and Technology (KIST), Seoul 02456, Republic of Korea
| | - Eunjung Kim
- Natural Product Systems Biology Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
| | - Hyun-Mee Park
- Advanced Analysis and Data Center, Korea Institute of Science and Technology (KIST), Seoul 02456, Republic of Korea
| | - Jae-Young Kim
- Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon 34134, Republic of Korea
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21
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Smith EM, Coughlan ML, Maday S. Turning garbage into gold: Autophagy in synaptic function. Curr Opin Neurobiol 2025; 90:102937. [PMID: 39667255 PMCID: PMC11903044 DOI: 10.1016/j.conb.2024.102937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 10/26/2024] [Accepted: 11/13/2024] [Indexed: 12/14/2024]
Abstract
Trillions of synapses in the human brain enable thought and behavior. Synaptic connections must be established and maintained, while retaining dynamic flexibility to respond to experiences. These processes require active remodeling of the synapse to control the composition and integrity of proteins and organelles. Macroautophagy (hereafter, autophagy) provides a mechanism to edit and prune the synaptic proteome. Canonically, autophagy has been viewed as a homeostatic process, which eliminates aged and damaged proteins to maintain neuronal survival. However, accumulating evidence suggests that autophagy also degrades specific cargoes in response to neuronal activity to impact neuronal transmission, excitability, and synaptic plasticity. Here, we will discuss the diverse roles, regulation, and mechanisms of neuronal autophagy in synaptic function and contributions from glial autophagy in these processes.
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Affiliation(s)
- Erin Marie Smith
- Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Maeve Louise Coughlan
- Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sandra Maday
- Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
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22
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Saca VR, Huber T, Sakmar TP. G protein-coupled receptor-targeted proteolysis-targeting chimeras in cancer therapeutics. Mol Pharmacol 2025; 107:100013. [PMID: 40023512 DOI: 10.1016/j.molpha.2024.100013] [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: 10/07/2024] [Accepted: 12/05/2024] [Indexed: 03/04/2025] Open
Abstract
G protein-coupled receptors (GPCRs) comprise a family of heptahelical membrane proteins that mediate intracellular and intercellular transmembrane signaling. Defects in GPCR signaling pathways are implicated in the pathophysiology of many diseases, including cardiovascular disease, endocrinopathies, immune disorders, and cancer. Although GPCRs are attractive drug targets, only a small number of Food and Drug Administration-approved anticancer therapeutics target GPCRs. Targeted protein degradation (TPD) technology allows for the direct modulation of the cellular expression level of a protein of interest. TPD methods such as proteolysis-targeting chimeras (PROTACs) use the ubiquitin-proteasome system to degrade a protein of interest selectively. Although the PROTAC system has not been widely applied to GPCRs and other membrane proteins, there is evidence that PROTACs or other TPD methods could be applied to the GPCRome. Current GPCR PROTACs show the feasibility of using PROTACs to degrade GPCRs; however, the degradation mechanism for some of these GPCR PROTACs is uncertain. Additional studies aimed at elucidating the degradation mechanism of GPCRs with PROTACs are necessary. Discovery of new allosteric intracellular small molecule binders of GPCRs will be required for the development of intracellularly oriented PROTACs. Promising early results in targeted degradation of GPCRs suggest that TPD drug discovery platforms will be useful in developing PROTACs targeting pathological GPCRs. SIGNIFICANCE STATEMENT: Aberrant signaling of G protein-coupled receptors (GPCRs) can contribute to the pathophysiology of cancer. Although GPCRs are generally highly attractive drug targets, many individual GPCRs are currently undrugged using traditional drug discovery approaches. Targeted protein degradation technologies, such as proteolysis-targeting chimeras, provide a new approach to drug discovery for targeting previously undruggable GPCRs relevant to the molecular pathophysiology of cancer.
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Affiliation(s)
- Victoria R Saca
- Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York; Tri-Institutional PhD Program in Chemical Biology, New York, New York
| | - Thomas Huber
- Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York
| | - Thomas P Sakmar
- Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York.
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23
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Pilcher C, Buco PAV, Truong JQ, Ramsland PA, Smeets MF, Walkley CR, Holien JK. Characteristics of the Kelch domain containing (KLHDC) subfamily and relationships with diseases. FEBS Lett 2025. [PMID: 39887712 DOI: 10.1002/1873-3468.15108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/08/2025] [Accepted: 01/13/2025] [Indexed: 02/01/2025]
Abstract
The Kelch protein superfamily is an evolutionary conserved family containing 63 alternate protein coding members. The superfamily is split into three subfamilies: Kelch like (KLHL), Kelch-repeat and bric-a-bracs (BTB) domain containing (KBTBD) and Kelch domain containing protein (KLHDC). The KLHDC subfamily is one of the smallest within the Kelch superfamily, containing 10 primary members. There is little known about the structures and functions of the subfamily; however, they are thought to be involved in several cellular and molecular processes. Recently, there have been significant structural and biochemical advances for KLHDC2, which has aided our understanding of other KLHDC family members. Furthermore, small molecules directly targeting KLHDC2 have been identified, which act as tools for targeted protein degradation. This review utilises this information, in conjunction with a thorough exploration of the structural aspects and potential biological functions to summarise the relationship between KLHDCs and human disease.
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Affiliation(s)
- Courtney Pilcher
- School of Science, STEM College, RMIT University, Melbourne, Australia
- St Vincent's Institute of Medical Research, Fitzroy, Australia
| | - Paula Armina V Buco
- St Vincent's Institute of Medical Research, Fitzroy, Australia
- Department of Medicine, Eastern Hill Academic Centre, Melbourne Medical School, The University of Melbourne, Carlton, Australia
| | - Jia Q Truong
- School of Science, STEM College, RMIT University, Melbourne, Australia
| | - Paul A Ramsland
- School of Science, STEM College, RMIT University, Melbourne, Australia
- Department of Immunology, Monash University, Melbourne, Australia
- Department of Surgery, Austin Health, The University of Melbourne, Melbourne, Australia
| | | | - Carl R Walkley
- St Vincent's Institute of Medical Research, Fitzroy, Australia
- Department of Medicine, Eastern Hill Academic Centre, Melbourne Medical School, The University of Melbourne, Carlton, Australia
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, Australia
- Department of Molecular and Translational Science, Monash University, Melbourne, Australia
| | - Jessica K Holien
- School of Science, STEM College, RMIT University, Melbourne, Australia
- St Vincent's Institute of Medical Research, Fitzroy, Australia
- Department of Medicine, Eastern Hill Academic Centre, Melbourne Medical School, The University of Melbourne, Carlton, Australia
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24
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Zhou L, Ullah F, Zou J, Zeng X. Molecular and Physiological Responses of Plants that Enhance Cold Tolerance. Int J Mol Sci 2025; 26:1157. [PMID: 39940925 PMCID: PMC11818088 DOI: 10.3390/ijms26031157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/17/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Low-temperature stress, including chilling and freezing injuries, significantly impacts plant growth in tropical and temperate regions. Plants respond to cold stress by activating mechanisms that enhance freezing tolerance, such as regulating photosynthesis, metabolism, and protein pathways and producing osmotic regulators and antioxidants. Membrane stability is crucial, with cold-resistant plants exhibiting higher lipid unsaturation to maintain fluidity and normal metabolism. Low temperatures disrupt reactive oxygen species (ROS) metabolism, leading to oxidative damage, which is mitigated by antioxidant defenses. Hormonal regulation, involving ABA, auxin, gibberellins, and others, further supports cold adaptation. Plants also manage osmotic balance by accumulating osmotic regulators like proline and sugars. Through complex regulatory pathways, including the ICE1-CBF-COR cascade, plants optimize gene expression to survive cold stress, ensuring adaptability to freezing conditions. This study reviews the recent advancements in genetic engineering technologies aimed at enhancing the cold resistance of agricultural crops. The goal is to provide insights for further improving plant cold tolerance and developing new cold-tolerant varieties.
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Affiliation(s)
- Lixia Zhou
- National Key Laboratory for Tropical Crop Breeding, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China;
- Hainan Key Laboratory of Tropical Oil Crops Biology, Coconut Research Institute, Chinese Academy of Tropical Agricultural Sciences, Wenchang 571339, China
| | - Fazal Ullah
- College of Life Sciences, Northwest Normal University, Lanzhou 730070, China;
| | - Jixin Zou
- National Key Laboratory for Tropical Crop Breeding, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China;
- Hainan Key Laboratory of Tropical Oil Crops Biology, Coconut Research Institute, Chinese Academy of Tropical Agricultural Sciences, Wenchang 571339, China
| | - Xianhai Zeng
- National Key Laboratory for Tropical Crop Breeding, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China;
- Hainan Key Laboratory of Tropical Oil Crops Biology, Coconut Research Institute, Chinese Academy of Tropical Agricultural Sciences, Wenchang 571339, China
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25
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Pun R, North BJ. Role of spindle assembly checkpoint proteins in gametogenesis and embryogenesis. Front Cell Dev Biol 2025; 12:1491394. [PMID: 39911185 PMCID: PMC11794522 DOI: 10.3389/fcell.2024.1491394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 12/17/2024] [Indexed: 02/07/2025] Open
Abstract
The spindle assembly checkpoint (SAC) is a surveillance mechanism that prevents uneven segregation of sister chromatids between daughter cells during anaphase. This essential regulatory checkpoint prevents aneuploidy which can lead to various congenital defects observed in newborns. Many studies have been carried out to elucidate the role of proteins involved in the SAC as well as the function of the checkpoint during gametogenesis and embryogenesis. In this review, we discuss the role of SAC proteins in regulating both meiotic and mitotic cell division along with several factors that influence the SAC strength in various species. Finally, we outline the role of SAC proteins and the consequences of their absence or insufficiency on proper gametogenesis and embryogenesis in vivo.
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Affiliation(s)
| | - Brian J. North
- Biomedical Sciences Department, School of Medicine, Creighton University, Omaha, NE, United States
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26
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Escuder-Rodríguez JJ, Rodríguez-Alonso A, Jove L, Quiroga M, Alfonsín G, Figueroa A. Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai. Cell Mol Biol Lett 2025; 30:9. [PMID: 39833727 PMCID: PMC11749156 DOI: 10.1186/s11658-025-00693-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025] Open
Abstract
Hakai protein (CBLL1 gene) was identified as an E3 ubiquitin ligase of E-cadherin complex, inducing its ubiquitination and degradation, thus inducing epithelial-to-mesenchymal transition. Most of the knowledge about the protein was associated to its E3 ubiquitin ligase canonical role. However, important recent published research has highlighted the noncanonical role of Hakai, independent of its E3 ubiquitin ligase activity, underscoring its involvement in the N6-methyladenosine (m6A) writer complex and its impact on the methylation of RNA. The involvement of Hakai in this mRNA modification process has renewed the relevance of this protein as an important contributor in cancer. Moreover, Hakai potential as a cancer biomarker and its prognostic value in malignant disease also emphasize its untapped potential in precision medicine, which would also be discussed in detail in our review. The development of the first small-molecule inhibitor that targets its atypical substrate binding domain is a promising step that could eventually lead to patient benefit, and we would cover its discovery and ongoing efforts toward its use in clinic.
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Affiliation(s)
- Juan-José Escuder-Rodríguez
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Xubias de Arriba 84, 15006, A Coruña, Spain
| | - Andrea Rodríguez-Alonso
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Xubias de Arriba 84, 15006, A Coruña, Spain
| | - Lía Jove
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Xubias de Arriba 84, 15006, A Coruña, Spain
| | - Macarena Quiroga
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Xubias de Arriba 84, 15006, A Coruña, Spain
| | - Gloria Alfonsín
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Xubias de Arriba 84, 15006, A Coruña, Spain
| | - Angélica Figueroa
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), Xubias de Arriba 84, 15006, A Coruña, Spain.
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27
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Xu H, Yin Q, Fan L, Zhao Y, Song B, Xu Q, Zhu J, Xu M. RNF138 contributes to cisplatin resistance in nasopharyngeal carcinoma cells. Sci Rep 2025; 15:1406. [PMID: 39789198 PMCID: PMC11718199 DOI: 10.1038/s41598-025-85716-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025] Open
Abstract
Resistance to chemotherapy is a significant concern in the treatment of nasopharyngeal carcinoma (NPC), and occurs due to various mechanisms. This study is aimed to evaluate the effects of RING finger protein 138 (RNF138) in the development of cisplatin resistance to NPC. After gene overexpression and silencing, the expression levels of RNF138 were evaluated. The impacts of RNF138 on the proliferation and apoptosis rate of NPC cells were then assessed. γ-H2AX-mediated DNA damage was determined via immunofluorescence assay. Moreover, a tumor xenograft mouse model was developed to investigate the role of RNF138 on NPC progression in vivo. Additionally, transcriptome analysis was performed in 5-8 F cells transfection with OE-RNF1138 or OE-NC.Cisplatin significantly inhibited the proliferation, and promoted apoptosis and DNA damage in NPC cells; however, overexpression of RNF138 reversed the aforementioned regulatory role of cisplatin on NPC cells. Knockdown of RNF138 resulted in contrasting phenotypic outcomes. Additionally, in nude mice, RNF138 overexpression attenuated the suppressive effects of cisplatin on the growth of xenograft tumor, while RNF138 silencing further enhanced the inhibiting role of cisplatin. We further indicated that in 5-8 F cells following RNF138 overexpression, some pathways such as PI3K-Akt signaling pathway, human papillomavirus infection and ErbB signaling pathway that have been reported to be associated with NPC progression and cisplatin resistance were significantly enriched. These findings indicate that the modulation of RNF138 could potentially address the issue of chemotherapy failure by overcoming cisplatin resistance in NPC cells, making it a promising candidate for targeted drug therapy.
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Affiliation(s)
- Hangyu Xu
- Department of Otolaryngology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, 318000, Zhejiang, China
| | - Qing Yin
- Department of Otolaryngology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, 318000, Zhejiang, China
| | - Linna Fan
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Yating Zhao
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), No. 999 Donghai Avenue, Taizhou City, 318000, Zhejiang Province, China
| | - Biying Song
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), No. 999 Donghai Avenue, Taizhou City, 318000, Zhejiang Province, China
| | - Qifan Xu
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), No. 999 Donghai Avenue, Taizhou City, 318000, Zhejiang Province, China
| | - Jie Zhu
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), No. 999 Donghai Avenue, Taizhou City, 318000, Zhejiang Province, China.
| | - Meifen Xu
- Department of Clinical Laboratory, Taizhou Central Hospital (Taizhou University Hospital), No. 999 Donghai Avenue, Taizhou City, 318000, Zhejiang Province, China.
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28
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Awan AB, Osman MJA, Khan OM. Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities. Cells 2025; 14:69. [PMID: 39851497 PMCID: PMC11763706 DOI: 10.3390/cells14020069] [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: 11/11/2024] [Revised: 12/16/2024] [Accepted: 12/24/2024] [Indexed: 01/26/2025] Open
Abstract
Ubiquitination is cells' second most abundant posttranslational protein modification after phosphorylation. The ubiquitin-proteasome system (UPS) is critical in maintaining essential life processes such as cell cycle control, DNA damage repair, and apoptosis. Mutations in ubiquitination pathway genes are strongly linked to the development and spread of multiple cancers since several of the UPS family members possess oncogenic or tumor suppressor activities. This comprehensive review delves into understanding the ubiquitin code, shedding light on its role in cancer cell biology and immune evasion. Furthermore, we highlighted recent advances in the field for targeting the UPS pathway members for effective therapeutic intervention against human cancers. We also discussed the recent update on small-molecule inhibitors and PROTACs and their progress in preclinical and clinical trials.
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Affiliation(s)
- Aiman B. Awan
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
| | - Maryiam Jama Ali Osman
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
- Research Branch, Sidra Medicine, Doha P.O. Box 34110, Qatar
| | - Omar M. Khan
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
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29
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Omar EA, R R, Das PK, Pal R, Purawarga Matada GS, Maji L. Next-generation cancer therapeutics: PROTACs and the role of heterocyclic warheads in targeting resistance. Eur J Med Chem 2025; 281:117034. [PMID: 39527893 DOI: 10.1016/j.ejmech.2024.117034] [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: 09/20/2024] [Revised: 10/30/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
One of the major obstacles to sustained cancer treatment effectiveness is the development of medication resistance. Current therapies that block proteins associated with cancer progression often lose their efficacy due to acquired drug resistance, which is frequently driven by mutated or overexpressed protein targets. Proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic strategy by hijacking the cell's ubiquitin-proteasome system to degrade disease-causing proteins, presenting several potential advantages. Over the past few years, PROTACs have been developed to target various cancer-related proteins, offering new treatment options for patients with previously untreatable malignancies and serving as a foundation for next-generation therapeutics. One of the notable benefits of PROTACs is their ability to overcome certain resistance mechanisms that limit the effectiveness of conventional targeted therapies, as shown in several recent studies. Additionally, research teams are investigating how PROTACs can selectively degrade mutant proteins responsible for resistance to first-line cancer therapies. In the pursuit of novel and effective treatments, this review highlights recent advancements in the development of PROTACs aimed at overcoming cancer resistance. When it comes to drug design, heterocyclic scaffolds often serve as a foundational framework, offering opportunities for modification and optimization of novel molecules. Researchers are similarly exploring various heterocyclic derivatives as "warheads" in the design of PROTACs has been instrumental in pushing the boundaries of targeted protein degradation. As warheads, these heterocyclic compounds are responsible for recognizing and binding to the target protein, which ultimately leads to its degradation via the ubiquitin-proteasome system. This study aims to provide a comprehensive overview of cutting-edge strategies in PROTAC design, offering detailed insights into key concepts and methodologies for creating effective PROTACs. Special emphasis is placed on structure-based rational design, the development of novel warheads, and their critical in influencing biological activity.
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Affiliation(s)
- Ebna Azizal Omar
- Centre for Excellence in Drug Analysis, Department of Pharmaceutical Analysis, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - Rajesh R
- Centre for Excellence in Drug Analysis, Department of Pharmaceutical Analysis, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India.
| | - Pronoy Kanti Das
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - Rohit Pal
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - Gurubasavaraja Swamy Purawarga Matada
- Integrated Drug Discovery Centre, Department of Pharmaceutical Chemistry, Acharya & BM Reddy College of Pharmacy, Bengaluru, 560107, Karnataka, India
| | - Lalmohan Maji
- Tarifa Memorial Institute of Pharmacy, Department of Pharmaceutical Chemistry, Murshidabad, 742166, West Bengal, India
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30
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Li H, Chen Y, Fu M, Wang L, Liu R, Liu Z. Systematic Analysis of Cotton RING E3 Ubiquitin Ligase Genes Reveals Their Potential Involvement in Salt Stress Tolerance. Int J Mol Sci 2025; 26:359. [PMID: 39796212 PMCID: PMC11720228 DOI: 10.3390/ijms26010359] [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: 11/29/2024] [Revised: 01/02/2025] [Accepted: 01/02/2025] [Indexed: 01/13/2025] Open
Abstract
The Really Interesting New Gene (RING) E3 ubiquitin ligases represent the largest class of E3 ubiquitin ligases involved in protein degradation and play a pivotal role in plant growth, development, and environmental responses. Despite extensive studies in numerous plant species, the functions of RING E3 ligases in cotton remain largely unknown. In this study, we performed systematic identification, characterization, and expression analysis of RING genes in cotton. A total of 514, 509, and 914 RING genes were identified in Gossypium arboretum, G. raimondii, and G. hirsutum, respectively. Duplication analysis indicates that segmental duplication may be the primary mechanism responsible for the expansion of the cotton RING gene family. Moreover, the Ka/Ks analysis suggests that these duplicated genes have undergone purifying selection throughout the evolutionary history of cotton. Notably, 393 G. hirsutum RING genes exhibited differential expression in response to salt stress. The overexpression of the specific C3H2C3 RING gene, GhZFRG1, in Arabidopsis resulted in enhanced tolerance to salt stress. This study contributes to our understanding of the evolution of cotton RING ligases and paves the way for further functional analysis of the RING E3 ligase genes in cotton.
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Affiliation(s)
| | | | | | | | | | - Zhanji Liu
- Key Laboratory of Cotton Breeding and Cultivation in Huang-Huai-Hai Plain, Ministry of Agriculture and Rural Affairs, Institute of Industrial Crops Shandong Academy of Agricultural Sciences, Jinan 250100, China; (H.L.); (Y.C.); (M.F.); (L.W.); (R.L.)
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31
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Bagde PH, Kandpal M, Rani A, Kumar S, Mishra A, Jha HC. Proteasomal Dysfunction in Cancer: Mechanistic Pathways and Targeted Therapies. J Cell Biochem 2025; 126:e70000. [PMID: 39887732 DOI: 10.1002/jcb.70000] [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: 07/02/2024] [Revised: 12/09/2024] [Accepted: 01/10/2025] [Indexed: 02/01/2025]
Abstract
Proteasomes are the catalytic complexes in eukaryotic cells that decide the fate of proteins involved in various cellular processes in an energy-dependent manner. The proteasomal system performs its function by selectively destroying the proteins labelled with the small protein ubiquitin. Dysfunctional proteasomal activity is allegedly involved in various clinical disorders such as cancer, neurodegenerative disorders, ageing, and so forth, making it an important therapeutic target. Notably, compared to healthy cells, cancer cells have a higher protein homeostasis requirement and a faster protein turnover rate. The ubiquitin-proteasome system (UPS) helps cancer cells increase rapidly and experience less apoptotic cell death. Therefore, understanding UPS is essential to design and discover some effective inhibitors for cancer therapy. Hereby, we have focused on the role of the 26S proteasome complex, mainly the UPS, in carcinogenesis and seeking potential therapeutic targets in treating numerous cancers.
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Affiliation(s)
- Pranit Hemant Bagde
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, Madhya Pradesh, India
| | - Meenakshi Kandpal
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, Madhya Pradesh, India
| | - Annu Rani
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, Madhya Pradesh, India
| | - Sachin Kumar
- Himalayan School of Biosciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology, Jodhpur, Rajasthan, India
| | - Hem Chandra Jha
- Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, Madhya Pradesh, India
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Gottfried Y, Lulu-Shimron C, Goldhirsh G, Fisher Y, Ziv T, Hoon DSB, Kravtsova-Ivantsiv Y, Ciechanover A. Vimentin is a ubiquitination and degradation substrate of the ubiquitin ligase KPC1. Biochem Biophys Res Commun 2024; 745:151231. [PMID: 39732122 DOI: 10.1016/j.bbrc.2024.151231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 12/20/2024] [Indexed: 12/30/2024]
Abstract
The ubiquitin proteasome system (UPS), driven by ubiquitin as a degradation signal, eliminates, in a highly specific manner, 'abnormal' proteins and proteins that completed their function. This process involves a hierarchical cascade of E1, E2, and E3 enzymes. The E3 ubiquitin ligases, act as specific receptors that bind their cognate substrates. We have previously shown that the ubiquitin ligase KPC1 possesses a strong tumor-suppressive characteristic caused by the p50 subunit of the NF-κB transcription factor, which is generated by limited, KPC1-mediated processing of its p105 precursor. In this study, we identified vimentin as a novel substrate of the KPC1. We demonstrated that the ligase forms a complex with vimentin and modifies it by ubiquitination. Overexpression of KPC1 in HEK293T cells downregulates vimentin expression. Conversely, deletion of KPC1 in HAP1 cells results in upregulation of vimentin. Importantly, we revealed both in vitro and in a tumor model in mice that at least part of this effect is mediated through the downregulation of vimentin. Furthermore, in human clear cell renal cell carcinoma (ccRCC) samples, we found a negative correlation between KPC1 and vimentin expression. Overall, we demonstrate that the KPC1 ubiquitin E3 ligase downregulates vimentin expression, thereby reducing migration and tumorigenicity of cancer cells.
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Affiliation(s)
- Yossi Gottfried
- The Rappaport Faculty of Medicine and Research Institute, and the Rappaport Technion Integrated Cancer Center (R-TICC), Technion-Israel Institute of Technology, Haifa, 3109601, Israel
| | - Chen Lulu-Shimron
- The Rappaport Faculty of Medicine and Research Institute, and the Rappaport Technion Integrated Cancer Center (R-TICC), Technion-Israel Institute of Technology, Haifa, 3109601, Israel
| | - Gilad Goldhirsh
- The Rappaport Faculty of Medicine and Research Institute, and the Rappaport Technion Integrated Cancer Center (R-TICC), Technion-Israel Institute of Technology, Haifa, 3109601, Israel
| | - Yael Fisher
- Institue of Pathology, Rambam Health Care Campus, Haifa, 3109601, Israel
| | - Tamar Ziv
- Smoler Proteomics Center, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Dave S B Hoon
- Department of Translational Molecular Medicine, Saint Johns Cancer Institute, PHS, Santa Monica, CA, 90025, USA
| | - Yelena Kravtsova-Ivantsiv
- The Rappaport Faculty of Medicine and Research Institute, and the Rappaport Technion Integrated Cancer Center (R-TICC), Technion-Israel Institute of Technology, Haifa, 3109601, Israel.
| | - Aaron Ciechanover
- The Rappaport Faculty of Medicine and Research Institute, and the Rappaport Technion Integrated Cancer Center (R-TICC), Technion-Israel Institute of Technology, Haifa, 3109601, Israel.
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Wu W, Yang J, Yu T, Zou Z, Huang X. The Role and Mechanism of TRIM Proteins in Gastric Cancer. Cells 2024; 13:2107. [PMID: 39768197 PMCID: PMC11674240 DOI: 10.3390/cells13242107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/13/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Tripartite motif (TRIM) family proteins, distinguished by their N-terminal region that includes a Really Interesting New Gene (RING) domain with E3 ligase activity, two B-box domains, and a coiled-coil region, have been recognized as significant contributors in carcinogenesis, primarily via the ubiquitin-proteasome system (UPS) for degrading proteins. Mechanistically, these proteins modulate a variety of signaling pathways, including Wnt/β-catenin, PI3K/AKT, and TGF-β/Smad, contributing to cellular regulation, and also impact cellular activities through non-signaling mechanisms, including modulation of gene transcription, protein degradation, and stability via protein-protein interactions. Currently, growing evidence indicates that TRIM proteins emerge as potential regulators in gastric cancer, exhibiting both tumor-suppressive and oncogenic roles. Given their critical involvement in cellular processes and the notable challenges of gastric cancer, exploring the specific contributions of TRIM proteins to this disease is necessary. Consequently, this review elucidates the roles and mechanisms of TRIM proteins in gastric cancer, emphasizing their potential as therapeutic targets and prognostic factors.
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Affiliation(s)
- Wangxi Wu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Jiangxi Provincial Key Laboratory of Bioengineering Drugs, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (W.W.); (T.Y.)
- The Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (J.Y.); (Z.Z.)
| | - Jinyu Yang
- The Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (J.Y.); (Z.Z.)
| | - Tian Yu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Jiangxi Provincial Key Laboratory of Bioengineering Drugs, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (W.W.); (T.Y.)
| | - Zhuoling Zou
- The Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (J.Y.); (Z.Z.)
| | - Xuan Huang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Jiangxi Provincial Key Laboratory of Bioengineering Drugs, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, China; (W.W.); (T.Y.)
- Chongqing Research Institute, Nanchang University, Chongqing 400010, China
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Behera A, Sachan D, Barik GK, Reddy ABM. Role of MARCH E3 ubiquitin ligases in cancer development. Cancer Metastasis Rev 2024; 43:1257-1277. [PMID: 39037545 DOI: 10.1007/s10555-024-10201-x] [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: 04/14/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024]
Abstract
Membrane-associated RING-CH (MARCH) E3 ubiquitin ligases, a family of RING-type E3 ubiquitin ligases, have garnered increased attention for their indispensable roles in immune regulation, inflammation, mitochondrial dynamics, and lipid metabolism. The MARCH E3 ligase family consists of eleven distinct members, and the dysregulation of many of these members has been documented in several human malignancies. Over the past two decades, extensive research has revealed that MARCH E3 ligases play pivotal roles in cancer progression by ubiquitinating key oncogenes and tumor suppressors and orchestrating various signaling pathways. Some MARCH E3s act as oncogenes, while others act as tumor suppressors, and the majority of MARCH E3s play both oncogenic and tumor suppressive roles in a context-dependent manner. Notably, there is special emphasis on the sole mitochondrial MARCH E3 ligase MARCH5, which regulates mitochondrial homeostasis within cancer cells. In this review, we delve into the diverse functions of MARCH E3 ligases across different cancer types, shedding light on the underlying molecular mechanisms mediating their effects, their regulatory effects on cancer and their potential as therapeutic targets.
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Affiliation(s)
- Abhayananda Behera
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Deepanshi Sachan
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Ganesh Kumar Barik
- Cancer Biology Division, National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind Road, Pune, Maharashtra, 411007, India
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Lopez AD, Debnath T, Pinch M, Hansen IA. Phosphoproteomics analyses of Aedes aegypti fat body reveals blood meal-induced signaling and metabolic pathways. Heliyon 2024; 10:e40060. [PMID: 39634388 PMCID: PMC11615488 DOI: 10.1016/j.heliyon.2024.e40060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/29/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024] Open
Abstract
The mosquito fat body is the principal source of yolk protein precursors (YPP) during mosquito egg development in female Aedes aegypti. To better understand the metabolic and signaling pathways involved in mosquito reproduction, we investigated changes in the mosquito fat body phosphoproteome at multiple time points after a blood meal. Using LC/MS, we identified 3570 phosphorylated proteins containing 14,551 individual phosphorylation sites. We observed protein phosphorylation changes in cellular pathways required for vitellogenesis, as well as proteins involved in primary cellular functions. Specifically, after a blood meal, proteins involved in ribosome synthesis, transcription, translation, and autophagy showed dynamic changes in their phosphorylation patterns. Our results provide new insight into blood meal-induced fat body dynamics and reveal potential proteins that can be targeted for interference with mosquito reproduction. Considering the devastating impact of mosquitoes on human health, worldwide, new approaches to control mosquitoes are urgently needed.
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Affiliation(s)
| | | | - Matthew Pinch
- New Mexico State University, Las Cruces, NM, 88003, USA
- The University of Texas at El Paso, El Paso, TX, 79968, USA
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Vikal A, Maurya R, Patel BB, Sharma R, Patel P, Patil UK, Das Kurmi B. Protacs in cancer therapy: mechanisms, design, clinical trials, and future directions. Drug Deliv Transl Res 2024:10.1007/s13346-024-01754-z. [PMID: 39614036 DOI: 10.1007/s13346-024-01754-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2024] [Indexed: 12/01/2024]
Abstract
Cancer develops as a result of changes in both genetic and epigenetic mechanisms, which lead to the activation of oncogenes and the suppression of tumor suppressor genes. Despite advancements in cancer treatments, the primary approach still involves a combination of chemotherapy, radiotherapy, and surgery, typically providing a median survival of approximately five years for patients. Unfortunately, these therapeutic interventions often bring about substantial side effects and toxicities, significantly impacting the overall quality of life for individuals undergoing treatment. Therefore, urgent need of research required which comes up with effective treatment of cancer. This review explores the transformative role of Proteolysis-Targeting Chimeras (PROTACs) in cancer therapy. PROTACs, an innovative drug development strategy, utilize the cell's protein degradation machinery to selectively eliminate disease-causing proteins. The review covers the historical background, mechanism of action, design, and structure of PROTACs, emphasizing their precision in targeting oncogenic proteins. The discussion extends to the challenges, nanotechnology applications, and ongoing clinical trials, showcasing promising results and clinical progress. The review concludes with insights into patents, future directions, and the potential impact of PROTACs in addressing dysregulated protein expression across various diseases. Overall, it provides a concise yet comprehensive overview for researchers, clinicians, and industry professionals involved in developing targeted therapies.
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Affiliation(s)
- Akash Vikal
- Department of Pharmaceutics, ISF College of Pharmacy, GT Road, Moga, 142001, Punjab, India
| | - Rashmi Maurya
- Department of Pharmaceutics, ISF College of Pharmacy, GT Road, Moga, 142001, Punjab, India
| | - Brij Bihari Patel
- Department of Respiratory Medicine, School of Excellence in Pulmonary Medicines, Netaji Subhash Chandra Bose Medical College, Jabalpur, 482003, Madhya Pradesh, India
| | - Rajeev Sharma
- Department of Pharmacy, Amity University, Gwalior, 474005, Madhya Pradesh, India
| | - Preeti Patel
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Moga, 142001, Punjab, India
| | - Umesh K Patil
- Department of Pharmaceutical Sciences, Dr. Hari Singh Gour University, Sagar, 470003, India
| | - Balak Das Kurmi
- Department of Pharmaceutics, ISF College of Pharmacy, GT Road, Moga, 142001, Punjab, India.
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Zhu W, Chen X, Zhang J, Xu C. Structure of the CUL1-RBX1-SKP1-FBXO4 SCF ubiquitin ligase complex. Biochem Biophys Res Commun 2024; 735:150811. [PMID: 39406020 DOI: 10.1016/j.bbrc.2024.150811] [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: 10/04/2024] [Accepted: 10/09/2024] [Indexed: 11/05/2024]
Abstract
Cullin-RING E3 ubiquitin ligases (CRLs) constitute the largest family of ubiquitin ligase and play important roles in regulation of proteostasis. Here we presented the cryo-EM structure of CRL1FBXO4, a member of Cullin-1 E3 ligase. CRL1FBXO4 adopts a homodimer architecture. Structural analysis revealed that in the CRL1FBXO4 protomer, the substrate recognition subunit FBXO4 interacts both the adaptor protein SKP1, and the scaffold protein CUL1 via hydrophobic and electrostatic interactions. Two FBXO4 forms a domain-swapped dimer in the CRL1FBXO4 structure, which constitutes the basis for the dimerization of CRL1FBXO4. Inspired by the cryo-EM density, we modeled the architecture of whole CRL1FBXO4 as a symmetrical dimer, which provides insights into CRL1FBXO4-medaited turnover of oncogene proteins.
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Affiliation(s)
- Wenjie Zhu
- MOE Key Laboratory for Membraneless Organelles & Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, PR China
| | - Xinyan Chen
- MOE Key Laboratory for Membraneless Organelles & Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, PR China
| | - Jiahai Zhang
- MOE Key Laboratory for Membraneless Organelles & Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, PR China.
| | - Chao Xu
- MOE Key Laboratory for Membraneless Organelles & Cellular Dynamics, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, PR China.
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Gong Y, Wei M, Cao X, Xu C, Jin J, Pei L, Li Y, Xiao H, Wu L. Mbnl1-mediated alternative splicing of circMlxipl regulates Rbbp6-involved ChREBP turnover to inhibit lipotoxicity-induced β-cell damage. Mol Med 2024; 30:229. [PMID: 39580381 PMCID: PMC11585089 DOI: 10.1186/s10020-024-00991-9] [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: 08/20/2024] [Accepted: 11/06/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Diabetes, a global epidemic, is the leading cause of mortality globally. The aim of this study is to get better understanding of pathophysiology of diabetes. METHODS Palmitic acid (PA)-treated β-cells, db/db mice and high fat diet (HFD)-fed mouse model of type 2 diabetes were established. H&E was used to assess the histological changes of pancreas. IHC, FISH, western blot or qRT-PCR was employed to detect the expression of key molecules in primary islets or lipotoxic β-cells. Cell behaviors were detected by MTT, EdU incorporation assay, TUNEL assay and glucose-induced insulin secretion (GSIS). The associations among circMlxipl, Mbnl1 and Rbbp6 were validated by RIP and RNA pull-down assays, and the direct binding between Hdac3 and Mbnl1 promoter was examined by ChIP and luciferase assays. Co-IP was employed to assess the interaction between ChREBP and Rbbp6, as well as the ubiquitination of ChREBP. RESULTS Hdac3 and ChREBP were upregulated, but Mbnl1 and circMlxipl were downregulated in islets from diabetic mice and lipotoxic β-cells. Mbnl1 overexpression protected against PA-induced impairments in lipotoxic β-cells through modulating back-splicing of circMlxipl and suppressing ChREBP. Hdac3 served as a transcriptional repressor of Mbnl1, and it was implicated in circMlxipl-mediated protection via regulating ChREBP expression in lipotoxic β-cells. Lack of circMlxipl inhibited Rbbp6-mediated ubiquitin-proteasomal degradation of ChREBP in lipotoxic β-cells. In vivo studies revealed that Hdac3 knockdown or Mbnl1 overexpression alleviated diabetes symptoms through circMlxipl-regulated ChREBP in diabetic mice. CONCLUSION Mbnl1-mediated alternative splicing of circMlxipl regulates Rbbp6-involved ChREBP turnover to inhibit lipotoxicity-induced β-cell damage.
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Affiliation(s)
- Yingying Gong
- Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Meilin Wei
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Xiaopei Cao
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Changliu Xu
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Jiewen Jin
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ling Pei
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Yanbing Li
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Haipeng Xiao
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Liting Wu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
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Shi Y, Wu C, Wang C, Shen Y, Jiang A, Cao K, Liu X, Jiang X, Lv Z. IRAK2 overexpression restrains prostate cancer progression by regulation of TRAF6 ubiquitination. Cell Signal 2024; 125:111508. [PMID: 39549822 DOI: 10.1016/j.cellsig.2024.111508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/22/2024] [Accepted: 11/11/2024] [Indexed: 11/18/2024]
Abstract
Prostate cancer is recognized as one of the most common tumors among men worldwide, yet the molecular mechanisms underlying its progression remain to be fully understood. In this study, we explored the role of interleukin-1 receptor-associated kinase 2 (IRAK2) in the progression of prostate cancer. We discovered that IRAK2 expression is downregulated in prostate cancer tissues and cells. Functional assays, including MTT, transwell assays, wound healing assays, and in vivo xenograft models, demonstrated that upregulation of IRAK2 significantly inhibited prostate cancer cell viability, migration, invasion, and tumor growth. Furthermore, we found that IRAK2 modulates the biological functions of prostate cancer by interacting with TNF receptor-associated factor 6 (TRAF6). Knockdown of TRAF6 reversed the suppressive effects of IRAK2 overexpression on prostate cancer cell progression. Additionally, IRAK2 was found to suppress the ubiquitination and degradation of TRAF6 in prostate cancer cells. IRAK2 also influenced the sensitivity of prostate cancer cells to docetaxel (DTX), and silencing IRAK2 reversed the anti-tumor effects of DTX on prostate cancer cells. Our findings suggest that IRAK2 functions as a tumor suppressor in prostate cancer and may serve as a potential therapeutic target for developing effective treatments for prostate cancer.
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Affiliation(s)
- Yunfeng Shi
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China
| | - Chengshuai Wu
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China
| | - Chengyue Wang
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China
| | - Ying Shen
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China
| | - Anqi Jiang
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China
| | - Kai Cao
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China
| | - Xiaowu Liu
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China
| | - Xinying Jiang
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China.
| | - Zhong Lv
- Urology Surgery, Wujin Hospital Affiliated with Jiangsu University, The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu Province, China.
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Vatté J, Bourdeau V, Ferbeyre G, Schmitzer AR. Effects of Biguanide-PROTACs in Pancreatic Cancer Cells. Molecules 2024; 29:5329. [PMID: 39598718 PMCID: PMC11596947 DOI: 10.3390/molecules29225329] [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: 10/01/2024] [Revised: 10/25/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
This study focuses on the synthesis of Biguanide-PROTACs, formed by conjugating the biguanide motif with a spacer and a ligand for recognition subunits of two E3 ubiquitin ligases. Evaluation of their activity on pancreatic cancer cell (KP4) proliferation established a correlation between membrane permeability and median effective concentration. Mechanistic insights revealed that only two compounds exhibited biguanide-like AMPK activation, while only one hydrophobic compound uniquely altered mitochondrial protein levels. The prospect of developing and expanding the Biguanide-PROTAC library holds several promises, offering potential insights into biguanide mechanisms and the creation of more potent anticancer agents. This study contributes to understanding the intricate interplay between compound structure, permeability, and anticancer activity, paving the way for targeted drug development in pancreatic cancer treatment.
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Affiliation(s)
- Julie Vatté
- Département de Chimie, Faculté des Arts et des Sciences, Université de Montréal, 1375 a. Thérèse Lavoie-Roux, Montréal, QC H2V 0B3, Canada
| | - Véronique Bourdeau
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H2V 0B3, Canada (G.F.)
| | - Gerardo Ferbeyre
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H2V 0B3, Canada (G.F.)
- Montréal Cancer Institute, CR-CHUM, Université de Montréal, Montréal, QC H2V 0B3, Canada
| | - Andreea R. Schmitzer
- Département de Chimie, Faculté des Arts et des Sciences, Université de Montréal, 1375 a. Thérèse Lavoie-Roux, Montréal, QC H2V 0B3, Canada
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Goyani S, Shukla S, Mane M, Saranga MV, Chandak N, Shinde A, Currim F, Singh J, Singh R. Mitochondrial E3 ligase TRIM71 affects mitochondrial complex assembly and sensitizes dopaminergic neuronal cells to apoptosis in Parkinson's Disease (PD). Int J Biochem Cell Biol 2024; 177:106689. [PMID: 39522935 DOI: 10.1016/j.biocel.2024.106689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/06/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
Parkinson's Disease (PD) is a chronic neurodegenerative disorder that impacts the substantia niagra region of the midbrain leading to impaired motor as well as non-motor symptoms of the central nervous system (CNS). Mitochondrial dysfunction has been characterized as the primary cause of dopaminergic neuronal loss, however, the molecular mechanisms leading to mitochondrial dysfunction are not completely understood. PARKIN, E3 ubiquitin ligase, plays a crucial role in maintaining mitochondrial quality control, albeit the role of other E3 ligases in regulating mitochondrial functions is not understood. In the current study, we explored the implication of TRIM71, E3 ubiquitin ligase, in the modulation of mitochondrial functions and neuronal death in PD stress conditions induced by rotenone and 6-OHDA. Ectopic expression of TRIM71 in SH-SY5Y dopaminergic neuronal cells sensitizes to PD stress-induced cell death, while its knock-down rescues neuronal cell death. TRIM71 turnover is enhanced in neurons under PD stress conditions. TRIM71 predominantly localizes on the outer mitochondrial membrane and translocation increases during PD stress conditions. TRIM71 regulates mitochondrial complex I and IV assembly and activity. TRIM71 knock-down decreases mitochondrial ROS and enhances ATP level as well as mitochondrial membrane potential in PD stress conditions. TRIM71-mediated mitochondrial ROS and cell death were rescued by mitoTEMPO, a mitochondrial-targeted antioxidant. Altogether, the evidence strongly suggests TRIM71-mediated modulation of mitochondrial functions and neuronal apoptosis in PD stress conditions.
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Affiliation(s)
- Shanikumar Goyani
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - Shatakshi Shukla
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - Minal Mane
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - M V Saranga
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - Nisha Chandak
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - Anjali Shinde
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - Fatema Currim
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - Jyoti Singh
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India
| | - Rajesh Singh
- Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara, Gujarat 390 002, India.
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Wang J, Ye J, Liu R, Chen C, Wang W. TRIM47 drives gastric cancer cell proliferation and invasion by regulating CYLD protein stability. Biol Direct 2024; 19:106. [PMID: 39516831 PMCID: PMC11546413 DOI: 10.1186/s13062-024-00555-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
The expression of TRIM47, a member of the TRIM protein and E3 ubiquitin ligase families, is elevated in various cancers, such as non-small cell lung cancer and colorectal cancer, and is linked to poor prognosis. This study aimed to investigate the role of TRIM47 in gastric cancer development. Using The Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD) dataset and analysis of 20 patient samples from our center, TRIM47 was found to be significantly up-regulated in gastric cancer tissues and associated with advanced N-stage and poor prognosis. We constructed stable TRIM47 knockdown and overexpressing gastric cancer cell lines. CCK8, EDU, colony formation, wound healing, and Transwell tests were used to evaluate the effects on cell proliferation, invasion, and migration. The results showed that TRIM47 knockdown inhibited the proliferation, migration and invasion of gastric cancer cells, while TRIM47 overexpression promoted these behaviors. These results were further confirmed in vivo. In the mechanism part, we found that TRIM47 interacts with CYLD protein. Moreover, TRIM47 promotes K48-linked ubiquitination, leading to the degradation of CYLD by the proteasome, thereby activating the NF-κB pathway and regulating the biological behavior of gastric cancer cells. Taken together, our study demonstrated that TRIM47 is involved in the proliferation and metastasis of gastric cancer through the CYLD/NF-κB pathway.
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Affiliation(s)
- Jianguo Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China
- Laboratory of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China
- Department of Hepatobiliary Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Jing Ye
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China
- Laboratory of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China
| | - Rongqiang Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China
- Laboratory of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China
| | - Chen Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China.
- Laboratory of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China.
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China.
- Laboratory of General Surgery, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, Hubei, 430060, PR China.
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43
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Kar A, Mukherjee S, Mukherjee S, Biswas A. Ubiquitin: A double-edged sword in hepatitis B virus-induced hepatocellular carcinoma. Virology 2024; 599:110199. [PMID: 39116646 DOI: 10.1016/j.virol.2024.110199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 07/26/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024]
Abstract
Hepatitis B virus is one of the leading causes behind the neoplastic transformation of liver tissue and associated mortality. Despite the availability of many therapies and vaccines, the pathogenic landscape of the virus remains elusive; urging the development of novel strategies based on the fundamental infectious and transformative modalities of the virus-host interactome. Ubiquitination is a widely observed post-translational modification of several proteins, which either regulates the proteins' turnover or impacts their functionalities. In recent years, ample amount of literature has accumulated regarding the ubiquitination dynamics of the HBV proteins as well as the host proteins during HBV infection and carcinogenesis; with direct and detailed characterization of the involvement of HBV in these processes. Interestingly, while many of these ubiquitination events restrict HBV life cycle and carcinogenesis, several others promote the emergence of hepatocarcinoma by putting the virus in an advantageous position. This review sums up the snowballing literature on ubiquitination-mediated regulation of the host-HBV crosstalk, with special emphasis on its influence on the establishment and progression of hepatocellular carcinoma on a molecular level. With the advent of cutting-edge ubiquitination-targeted therapeutic approaches, the findings emanating from this review may potentiate the identification of novel anti-HBV targets for the formulation of novel anticancer strategies to control the HBV-induced hepato-carcinogenic process on a global scale.
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Affiliation(s)
- Arpita Kar
- Department of Signal Transduction & Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Sandipan Mukherjee
- Department of Signal Transduction & Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India
| | - Soumyadeep Mukherjee
- Department of in Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India
| | - Avik Biswas
- Department of Signal Transduction & Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India.
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Verma S, Ghatak A. Involvement of E3 Ubiquitin Ligases in Viral Infections of the Human Host. Viral Immunol 2024; 37:419-431. [PMID: 39469796 DOI: 10.1089/vim.2024.0068] [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: 10/30/2024] Open
Abstract
Viral infections are one of the principal causes of global primary health crises, with increased rate of infection and mortality demonstrated by the newer progeny of viruses. Viral invasion of the host involves utilization of various cellular machinery. Ubiquitination is one of a few central regulatory systems used by viruses for establishment of the infections in the host. Members of the ubiquitination system are involved in carrying out proteasomal degradation or functional modification of proteins in numerous cellular processes. E3 ubiquitin ligases play a major role in this system through recognition and recruitment of protein substrates and catalyzing the transfer of ubiquitin to these substrates. The versatility of ubiquitin ligases frequently makes them useful tools for the viruses, for either utilizing or degrading other cellular machineries, for carrying out their multiplication or inactivating the defensive strategies of the host. Therefore, these ligases are important targets for aiming at major pathways causing viral protein degradation or functional modification of the infection process. In this review, we have discussed the role and mechanism of different types of ubiquitin ligases in the context of infections of mainly human viruses, highlighting the viral proteins directly interacting with the ligases. Knowledge about these direct interactions is central in understanding the ubiquitin-dependent processes. This comprehensive account may also be beneficial for pharmaceutical exploration of E3 ligase-based broad-spectrum antiviral treatment.
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Affiliation(s)
- Suchanda Verma
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, India
| | - Archana Ghatak
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, India
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45
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Sreepangi S, Baha H, Opoku LA, Jones NX, Konadu M, Alem F, Barrera MD, Narayanan A. Host-Driven Ubiquitination Events in Vector-Transmitted RNA Virus Infections as Options for Broad-Spectrum Therapeutic Intervention Strategies. Viruses 2024; 16:1727. [PMID: 39599842 PMCID: PMC11599102 DOI: 10.3390/v16111727] [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: 06/11/2024] [Revised: 10/30/2024] [Accepted: 10/31/2024] [Indexed: 11/29/2024] Open
Abstract
Many vector-borne viruses are re-emerging as public health threats, yet our understanding of the virus-host interactions critical for productive infection remains limited. The ubiquitination of proteins, including host- and pathogen-derived proteins is a highly prominent and consistent post-translational modification that regulates protein function through signaling and degradation. Viral proteins are documented to hijack the host ubiquitination machinery to modulate multiple host processes including antiviral defense mechanisms. The engagement of the host ubiquitination machinery in the post-translational modification of viral proteins to support aspects of the viral life cycle including assembly and egress is also well documented. Exploring the role ubiquitination plays in the life cycle of vector-transmitted viral pathogens will increase the knowledge base pertinent to the impact of host-enabled ubiquitination of viral and host proteins and the consequences on viral pathogenesis. In this review, we explore E3 ligase-regulated ubiquitination pathways functioning as proviral and viral restriction factors in the context of acutely infectious, vector-transmitted viral pathogens and the potential for therapeutically targeting them for countermeasures development.
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Affiliation(s)
- Sanskruthi Sreepangi
- School of Systems Biology, College of Science, George Mason University, Fairfax, VA 22030, USA; (S.S.); (H.B.); (L.A.O.); (N.X.J.); (M.K.); (M.D.B.)
| | - Haseebullah Baha
- School of Systems Biology, College of Science, George Mason University, Fairfax, VA 22030, USA; (S.S.); (H.B.); (L.A.O.); (N.X.J.); (M.K.); (M.D.B.)
| | - Lorreta Aboagyewa Opoku
- School of Systems Biology, College of Science, George Mason University, Fairfax, VA 22030, USA; (S.S.); (H.B.); (L.A.O.); (N.X.J.); (M.K.); (M.D.B.)
| | - Naomi X. Jones
- School of Systems Biology, College of Science, George Mason University, Fairfax, VA 22030, USA; (S.S.); (H.B.); (L.A.O.); (N.X.J.); (M.K.); (M.D.B.)
| | - Maame Konadu
- School of Systems Biology, College of Science, George Mason University, Fairfax, VA 22030, USA; (S.S.); (H.B.); (L.A.O.); (N.X.J.); (M.K.); (M.D.B.)
| | - Farhang Alem
- Institute of Biohealth Innovation, George Mason University, Fairfax, VA 22030, USA;
| | - Michael D. Barrera
- School of Systems Biology, College of Science, George Mason University, Fairfax, VA 22030, USA; (S.S.); (H.B.); (L.A.O.); (N.X.J.); (M.K.); (M.D.B.)
| | - Aarthi Narayanan
- Department of Biology, College of Science, George Mason University, Fairfax, VA 22030, USA
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Pellman J, Goldstein A, Słabicki M. Human E3 ubiquitin ligases: accelerators and brakes for SARS-CoV-2 infection. Biochem Soc Trans 2024; 52:2009-2021. [PMID: 39222407 PMCID: PMC11555711 DOI: 10.1042/bst20230324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/12/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024]
Abstract
E3 ubiquitin ligases regulate the composition of the proteome. These enzymes mono- or poly-ubiquitinate their substrates, directly altering protein function or targeting proteins for degradation by the proteasome. In this review, we discuss the opposing roles of human E3 ligases as effectors and targets in the evolutionary battle between host and pathogen, specifically in the context of SARS-CoV-2 infection. Through complex effects on transcription, translation, and protein trafficking, human E3 ligases can either attenuate SARS-CoV-2 infection or become vulnerabilities that are exploited by the virus to suppress the host's antiviral defenses. For example, the human E3 ligase RNF185 regulates the stability of SARS-CoV-2 envelope protein through the ubiquitin-proteasome pathway, and depletion of RNF185 significantly increases SARS-CoV-2 viral titer (iScience (2023) 26, 106601). We highlight recent advances that identify functions for numerous human E3 ligases in the SARS-CoV-2 life cycle and we assess their potential as novel antiviral agents.
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Affiliation(s)
- Jesse Pellman
- Broad Institute of MIT and Harvard, Cambridge, MA, U.S.A
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S.A
| | - Anna Goldstein
- Broad Institute of MIT and Harvard, Cambridge, MA, U.S.A
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S.A
| | - Mikołaj Słabicki
- Broad Institute of MIT and Harvard, Cambridge, MA, U.S.A
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S.A
- Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, U.S.A
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47
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Jiang L, Qi X, Lai M, Zhou J, Yuan M, You J, Liu Q, Pan J, Zhao L, Ying M, Ji J, Li K, Zhang Y, Pan W, He Q, Yang B, Cao J. WDR20 prevents hepatocellular carcinoma senescence by orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc. Proc Natl Acad Sci U S A 2024; 121:e2407904121. [PMID: 39432777 PMCID: PMC11536108 DOI: 10.1073/pnas.2407904121] [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: 04/19/2024] [Accepted: 08/16/2024] [Indexed: 10/23/2024] Open
Abstract
The dysfunction of the ubiquitin-proteasome system (UPS) facilitates the malignant progression of hepatocellular carcinoma (HCC). While targeting the UPS for HCC therapy has been proposed, identifying effective targets has been challenging. In this study, we conducted a focused screen of siRNA libraries targeting UPS-related WD40 repeat (WDR) proteins and found that silencing WDR20, a deubiquitinating enzyme activating factor, selectively inhibited the proliferation of HCC cells without affecting normal hepatocytes. Moreover, the downregulation of WDR20 expression induced HCC cellular senescence and suppressed tumor progression in xenograft, sleeping beauty transposon/transposase, and hydrodynamic tail vein injection-induced HCC models, and Alb-Cre+/MYC+ HCC transgenic mouse models. Mechanistically, we found that WDR20 silencing disturbed the protein stability of c-Myc, orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc, thereby promoting the transcriptional activation of CDKN1A. Further investigation revealed a positive coexpression of WDR20 and c-Myc in a tissue microarray with 88 HCC clinical samples. By employing three patient-derived organoids from individuals with HCC, we have validated the decrease in c-Myc expression and the significant induction of senescence and growth inhibition following silencing of WDR20. This study not only uncovers the biological function of WDR20 and elucidates the molecular mechanism underlying its negative regulation of HCC cellular senescence but also highlight the potential of WDR20 as a promising target for HCC therapy.
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Affiliation(s)
- Li Jiang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
- The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou310018, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
| | - Xuxin Qi
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
| | - Minshan Lai
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
| | - Jiahao Zhou
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
| | - Meng Yuan
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
- The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou310018, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
| | - Jieqiong You
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
| | - Qiang Liu
- Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou310006, China
| | - Jinchang Pan
- Life Sciences Institute, Zhejiang University, Hangzhou310058, China
| | - Luyao Zhao
- Key Laboratory of Biotechnology of Antibiotic of National Health Commission, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100730, China
| | - Meidan Ying
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou310018, China
| | - Junfang Ji
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Life Sciences Institute, Zhejiang University, Hangzhou310058, China
- Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing312099, China
| | - Ke Li
- Key Laboratory of Biotechnology of Antibiotic of National Health Commission, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100730, China
| | - Yan Zhang
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou310016, China
- Department of Pharmacology and Department of Pathology of Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou310016, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou311113, China
- Center for Structural Pharmacology and Therapeutics Development, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou310016, China
- Frontier Science Center for Brain Research and Brain-Machine Integration of Ministry of Education, Zhejiang University School of Medicine, Hangzhou310058, China
| | - Weiwei Pan
- Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing314001, China
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
- The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou310018, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou310018, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
- The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou310018, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou310018, China
- School of Medicine, Hangzhou City University, Hangzhou310015, China
| | - Ji Cao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou310058, China
- The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou310018, China
- Cancer Center, Zhejiang University, Hangzhou310058, China
- Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou310018, China
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou310009, China
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Xiong D, Qiu Y, Zhao J, Zhou Y, Lee D, Gupta S, Torres M, Lu W, Liang S, Kang JJ, Eng C, Loscalzo J, Cheng F, Yu H. A structurally informed human protein-protein interactome reveals proteome-wide perturbations caused by disease mutations. Nat Biotechnol 2024:10.1038/s41587-024-02428-4. [PMID: 39448882 DOI: 10.1038/s41587-024-02428-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 09/11/2024] [Indexed: 10/26/2024]
Abstract
To assist the translation of genetic findings to disease pathobiology and therapeutics discovery, we present an ensemble deep learning framework, termed PIONEER (Protein-protein InteractiOn iNtErfacE pRediction), that predicts protein-binding partner-specific interfaces for all known protein interactions in humans and seven other common model organisms to generate comprehensive structurally informed protein interactomes. We demonstrate that PIONEER outperforms existing state-of-the-art methods and experimentally validate its predictions. We show that disease-associated mutations are enriched in PIONEER-predicted protein-protein interfaces and explore their impact on disease prognosis and drug responses. We identify 586 significant protein-protein interactions (PPIs) enriched with PIONEER-predicted interface somatic mutations (termed oncoPPIs) from analysis of approximately 11,000 whole exomes across 33 cancer types and show significant associations of oncoPPIs with patient survival and drug responses. PIONEER, implemented as both a web server platform and a software package, identifies functional consequences of disease-associated alleles and offers a deep learning tool for precision medicine at multiscale interactome network levels.
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Grants
- R01GM124559 U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- R01GM125639 U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- R01GM130885 U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- RM1GM139738 U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- R01DK115398 U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)
- U01HG007691 U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
- R01HL155107 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R01HL155096 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R01HL166137 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- U54HL119145 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- AHA957729 American Heart Association (American Heart Association, Inc.)
- 24MERIT1185447 American Heart Association (American Heart Association, Inc.)
- R01AG084250 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
- R56AG074001 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
- U01AG073323 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
- R01AG066707 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
- R01AG076448 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
- R01AG082118 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
- RF1AG082211 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
- R21AG083003 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
- RF1NS133812 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
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Affiliation(s)
- Dapeng Xiong
- Department of Computational Biology, Cornell University, Ithaca, NY, USA
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA
- Center for Innovative Proteomics, Cornell University, Ithaca, NY, USA
| | - Yunguang Qiu
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Junfei Zhao
- Department of Systems Biology, Herbert Irving Comprehensive Center, Columbia University, New York, NY, USA
| | - Yadi Zhou
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Dongjin Lee
- Department of Computational Biology, Cornell University, Ithaca, NY, USA
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA
| | - Shobhita Gupta
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA
- Center for Innovative Proteomics, Cornell University, Ithaca, NY, USA
- Biophysics Program, Cornell University, Ithaca, NY, USA
| | - Mateo Torres
- Department of Computational Biology, Cornell University, Ithaca, NY, USA
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA
- Center for Innovative Proteomics, Cornell University, Ithaca, NY, USA
| | - Weiqiang Lu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Siqi Liang
- Department of Computational Biology, Cornell University, Ithaca, NY, USA
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA
| | - Jin Joo Kang
- Department of Computational Biology, Cornell University, Ithaca, NY, USA
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA
- Center for Innovative Proteomics, Cornell University, Ithaca, NY, USA
| | - Charis Eng
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Joseph Loscalzo
- Channing Division of Network Medicine, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Feixiong Cheng
- Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
| | - Haiyuan Yu
- Department of Computational Biology, Cornell University, Ithaca, NY, USA.
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA.
- Center for Innovative Proteomics, Cornell University, Ithaca, NY, USA.
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49
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Shen K, Zhang Q. Literature review: nuclear factor kappa B (NF-κB) regulation in human cancers mediated by ubiquitin-specific proteases (USPs). ANNALS OF TRANSLATIONAL MEDICINE 2024; 12:90. [PMID: 39507445 PMCID: PMC11534757 DOI: 10.21037/atm-24-32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/28/2024] [Indexed: 11/08/2024]
Abstract
Background and Objective The nuclear factor kappa B (NF-κB) consists of a group of transcription factors of which its dysregulation is responsible for diseases such as inflammation and cancer. Ubiquitin-specific proteases (USPs) are the most prominent group among the deubiquitinases (DUBs). Their functions include control of protein stability and regulation of signaling transduction. The association between NF-κB activity and human cancer progression is evident. Still, the role of USPs in the NF-κB regulation in human cancers, especially prostate cancer, is not well understood. This review discusses on the role of USP-mediated regulation of the canonical NF-κB signaling pathway in human cancers and provides a prospect of future studies in prostate cancers. Methods Within the biomedical literature database, PubMed, our review team searched for keywords including USP, NF-κB signaling pathway, cancer, prostate cancer, and specific USPs such as USP1, USP2, USP3, etc. These keywords were used individually or in combinations. After screening, only mechanistic studies and articles reporting the subsequent changes in cellular behaviors were included for full-text review. Key Content and Findings Most USPs function primarily as DUBs to regulate the canonical NF-κB signaling pathway. The typical K48- and K63-linked DUB activities of USPs are the best understood. These USPs are positive and negative regulators of the NF-κB activity. However, their DUB activities against polyubiquitin chains with atypical linkages have not yet been extensively studied. Furthermore, some USPs can regulate the canonical NF-κB signaling pathway via ubiquitin-independent mechanisms. Conclusions In the regulation of the canonical NF-κB pathway, the USPs function primarily as DUBs, but they also regulate the p65/p50 by ubiquitin-independent mechanisms. Generally, in human cancer models, USP-mediated elevation and suppression of p65/p50 activity lead to more or less malignant cellular behaviors, respectively. Given the currently unbalanced focus on K48- and K63-linked DUB activities and the context-dependent function of USPs, future research of USP-mediated NF-κB regulation in human cancers should invest more in the DUB activities against the atypical polyubiquitin chains and test known mechanisms in different cancer models.
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Affiliation(s)
- Keyi Shen
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Qiuyang Zhang
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA
- Tulane Center for Aging, Tulane University, New Orleans, LA, USA
- Tulane Cancer Center and Louisiana Cancer Research Center, Tulane University, New Orleans, LA, USA
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Kwon JH, Kim SH. YBX1 promotes epithelial-mesenchymal transition in hepatocellular carcinoma via transcriptional regulation of PLRG1. Med Oncol 2024; 41:280. [PMID: 39400789 DOI: 10.1007/s12032-024-02516-0] [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: 08/12/2024] [Accepted: 09/20/2024] [Indexed: 10/15/2024]
Abstract
Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer worldwide. The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression, contributing to increased malignancy. While Pleiotropic Regulator 1 (PLRG1) is upregulated in HCC and is associated with enhanced cell proliferation, its oncogenic role in EMT remains unclear. In this study, we demonstrate that PLRG1 promotes EMT in HCC cells. Knockdown of PLRG1 in Huh7 cells resulted in decreased expression of the EMT markers N-cadherin and Snail, and impaired cell migration and invasion. Chromatin immunoprecipitation (ChIP) and luciferase assays identified Y-box binding protein 1 (YBX1) as a direct regulator of PLRG1 transcription, binding to its promoter region. Overexpression of YBX1 in SNU-449 cells led to increased PLRG1 expression and subsequent EMT activation, as well as enhanced migration, and invasion. These effects were attenuated by PLRG1 knockdown. Our findings indicate that YBX1 drives EMT in HCC by upregulating PLRG1, offering novel insights into the molecular mechanisms underlying HCC progression.
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Affiliation(s)
- Jae Hwan Kwon
- Department of Biology, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Sang Hoon Kim
- Department of Biology, Kyung Hee University, Seoul, 02447, Republic of Korea.
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