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Ubc9-Mediated SUMOylation of RPL3, an Unappreciated Mechanism against Hepatocyte Senescence by Repressing the DHX9-p16 Axis.

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Τίτλος: Ubc9-Mediated SUMOylation of RPL3, an Unappreciated Mechanism against Hepatocyte Senescence by Repressing the DHX9-p16 Axis.
Συγγραφείς: Xie H; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.; Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China., Gao Z; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Liu X; Department of Interventional Radiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China., Zhang S; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Wang Y; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Gao J; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Qi P; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zhang L; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zhao J; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Xiong T; Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Huang T; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.; Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Song J; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.; Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China., Yu Q; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Zhang S; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Liu Y; The Center for Obesity and Metabolic Health, Affiliated Hospital of Southwest Jiaotong University, the Third People's Hospital of Chengdu, 82 Qinglong Road, Chengdu, Sichuan, 610031, China., Yang P; Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, 030032, China., Al-Motawa MS; Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha, 34110, Qatar., Gong Q; Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei, 434023, China., Dong J; Organ Transplant Center, Shanghai Changzheng Hospital (Second Affiliated Hospital of Naval Medical University), Shanghai, 200003, China., Yin H; Organ Transplant Center, Shanghai Changzheng Hospital (Second Affiliated Hospital of Naval Medical University), Shanghai, 200003, China., Sun F; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.; Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha, 34110, Qatar., Liu S; Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, 030032, China., Wang CY; Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, 030032, China.; Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Doha, 34110, Qatar.; The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Wuhan, 430030, China.
Πηγή: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2026 Jan; Vol. 13 (1), pp. e10240. Date of Electronic Publication: 2025 Oct 20.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE
Imprint Name(s): Original Publication: Weinheim : WILEY-VCH, [2014]-
Ιατρικοί όροι (MeSH): Hepatocytes*/metabolism , Sumoylation*/genetics , Sumoylation*/physiology , Ubiquitin-Conjugating Enzymes*/metabolism , Ubiquitin-Conjugating Enzymes*/genetics , Cellular Senescence*/genetics , Cellular Senescence*/physiology , Ribosomal Proteins*/metabolism , Ribosomal Proteins*/genetics , Cyclin-Dependent Kinase Inhibitor p16*/metabolism , Cyclin-Dependent Kinase Inhibitor p16*/genetics , DEAD-box RNA Helicases*/metabolism , DEAD-box RNA Helicases*/genetics, Liver/metabolism ; Ubiquitin-Conjugating Enzyme UBC9 ; Animals ; Mice ; Humans ; Male ; Mice, Inbred C57BL ; Ribosomal Protein L3
Περίληψη: Although Ubc9-mediated SUMOylation are recognized to regulate the multiple aspects of hepatic biological processes, its impact on hepatic senescence and metabolic dysfunction-associated steatotic liver disease (MASLD), however, is yet to be fully addressed. Herein noted an age-dependent decrease of hepatic Ubc9 expression is first noted along with an escalated decrease of protein SUMOylation, which is coupled with enhanced senescent marker expressions both in humans and mice. Interestingly, Ubc9 is dispensable for liver development at the embryonic stage. However, Ubc9 deficiency in hepatocytes rendered mice with an exacerbated hepatic aging phenotype and more susceptible to fatty liver disease and steatohepatitis following the challenge of a methionine- and choline-deficient (MCD)-diet. Ii is further demonstrated that nuclear ribosomal protein L3 (RPL3) interacts with DExD/H-box (DDX/DHX) helicases (DHX9), which then recruits RNA polymerase II to the p16 promoter to transcribe its expression, thereby exacerbating the hepatocyte aging process. However, Ubc9-mediated SUMOylation prevents RPL3 nuclear translocation, by which it represses the expression of senescent markers such as p16 to attenuate the hepatic aging process. Together, the study highlights that Ubc9-mediated SUMOylation of RPL3 could be an unappreciated mechanism against hepatic aging in clinical settings.
(© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
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Grant Information: 2022YFA0806101 National Key R&D Program of China; 82130023 National Natural Science Foundation of China; 81920108009 National Natural Science Foundation of China; 82070808 National Natural Science Foundation of China; 82270885 82270893 National Natural Science Foundation of China; 82501021 National Natural Science Foundation of China; 202104010910009 Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province; 2021yjsCXCY097 Fundamental Research Funds for the Central Universities, HUST; 2024AOXIANG03 Research and Innovative Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital; 2024GSPYJ10 Continuous Funding Program for High-Level Research Achievements at Shanxi Bethune Hospital; 2024GSPYJ13 Continuous Funding Program for High-Level Research Achievements at Shanxi Bethune Hospital
Contributed Indexing: Keywords: DHX9; SUMOylation; aging; metabolic dysfunction‐associated steatotic liver disease (MASLD); ribosomal protein L3 (RPL3)
Substance Nomenclature: EC 6.3.2.- (Ubiquitin-Conjugating Enzyme UBC9)
EC 2.3.2.23 (Ubiquitin-Conjugating Enzymes)
0 (Ribosomal Proteins)
0 (Cyclin-Dependent Kinase Inhibitor p16)
EC 3.6.4.13 (DEAD-box RNA Helicases)
0 (Rpl3 protein, mouse)
0 (Ribosomal Protein L3)
Entry Date(s): Date Created: 20251020 Date Completed: 20260105 Latest Revision: 20260127
Update Code: 20260130
PubMed Central ID: PMC12767081
DOI: 10.1002/advs.202510240
PMID: 41114463
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2198-3844
DOI:10.1002/advs.202510240