USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377
Alcoholic cardiomyopathy (ACM) is a type of dilated cardiomyopathy unrelated to ischemia, which develops as a consequence of chronic alcohol consumption. While ethanol-induced irreversible cardiomyocyte death is implicated in ACM development and progression, the precise molecular mechanisms involved...
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0823 |
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| author | Jichen Pan Xiaolin Liu Xiao Li Shanshan Wang Yuliang Zhao Chong Yuan Dongdong Liu Liyan Wang Meng Zhang Fengming Liu Mei Zhang Shen Dai |
| author_facet | Jichen Pan Xiaolin Liu Xiao Li Shanshan Wang Yuliang Zhao Chong Yuan Dongdong Liu Liyan Wang Meng Zhang Fengming Liu Mei Zhang Shen Dai |
| author_sort | Jichen Pan |
| collection | DOAJ |
| description | Alcoholic cardiomyopathy (ACM) is a type of dilated cardiomyopathy unrelated to ischemia, which develops as a consequence of chronic alcohol consumption. While ethanol-induced irreversible cardiomyocyte death is implicated in ACM development and progression, the precise molecular mechanisms involved are still obscure. In the current study, we demonstrate that ethanol exposure promotes receptor-interacting serine/threonine-protein kinase 1 (RIPK1) autophosphorylation and enhances pRIPK1-associated apoptosis and necroptosis in ACM models both in vivo and in vitro. Through co-immunoprecipitation (Co-IP) combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis, we identified ubiquitin-specific protease 53 (USP53) as a pivotal deubiquitinase involved in modulating RIPK1 activation following ethanol stimulation in cardiomyocytes. Mechanistically, we found that ethanol induced up-regulation of USP53 via transcriptional induction by early growth response 1 (EGR1). Subsequently, USP53 interacted with the intermediate domain of RIPK1 and removed K63-linked ubiquitination at lysine-377 (K377), facilitating RIPK1 phosphorylation and triggering downstream apoptotic and necroptotic pathways in cardiac cells. Further, alcohol-fed cardiomyocyte-specific USP53 knockout (USP53CKO) mice exhibited improved survival rates and less cardiomyocyte death in hearts compared with the control group. Our study identifies USP53 as a novel regulator of RIPK1-dependent cell death and advances our understanding of the mechanistic pathways of ACM. These results highlight the USP53–RIPK1 signaling axis as a potential therapeutic target for mitigating ACM progression. |
| format | Article |
| id | doaj-art-66d335b4626e4e84b1d8f6aa6a47e0ba |
| institution | Kabale University |
| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj-art-66d335b4626e4e84b1d8f6aa6a47e0ba2025-08-20T04:01:00ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0823USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377Jichen Pan0Xiaolin Liu1Xiao Li2Shanshan Wang3Yuliang Zhao4Chong Yuan5Dongdong Liu6Liyan Wang7Meng Zhang8Fengming Liu9Mei Zhang10Shen Dai11State 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 250012, China.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 250012, China.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 250012, China.School of Basic Medical Sciences, Shandong University, Jinan 250012, China.School of Basic Medical Sciences, Shandong University, Jinan 250012, China.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 250012, China.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 250012, China.Morphological Experimental Center, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.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 250012, China.School of Basic Medical Sciences, Shandong University, Jinan 250012, China.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 250012, China.School of Basic Medical Sciences, Shandong University, Jinan 250012, China.Alcoholic cardiomyopathy (ACM) is a type of dilated cardiomyopathy unrelated to ischemia, which develops as a consequence of chronic alcohol consumption. While ethanol-induced irreversible cardiomyocyte death is implicated in ACM development and progression, the precise molecular mechanisms involved are still obscure. In the current study, we demonstrate that ethanol exposure promotes receptor-interacting serine/threonine-protein kinase 1 (RIPK1) autophosphorylation and enhances pRIPK1-associated apoptosis and necroptosis in ACM models both in vivo and in vitro. Through co-immunoprecipitation (Co-IP) combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis, we identified ubiquitin-specific protease 53 (USP53) as a pivotal deubiquitinase involved in modulating RIPK1 activation following ethanol stimulation in cardiomyocytes. Mechanistically, we found that ethanol induced up-regulation of USP53 via transcriptional induction by early growth response 1 (EGR1). Subsequently, USP53 interacted with the intermediate domain of RIPK1 and removed K63-linked ubiquitination at lysine-377 (K377), facilitating RIPK1 phosphorylation and triggering downstream apoptotic and necroptotic pathways in cardiac cells. Further, alcohol-fed cardiomyocyte-specific USP53 knockout (USP53CKO) mice exhibited improved survival rates and less cardiomyocyte death in hearts compared with the control group. Our study identifies USP53 as a novel regulator of RIPK1-dependent cell death and advances our understanding of the mechanistic pathways of ACM. These results highlight the USP53–RIPK1 signaling axis as a potential therapeutic target for mitigating ACM progression.https://spj.science.org/doi/10.34133/research.0823 |
| spellingShingle | Jichen Pan Xiaolin Liu Xiao Li Shanshan Wang Yuliang Zhao Chong Yuan Dongdong Liu Liyan Wang Meng Zhang Fengming Liu Mei Zhang Shen Dai USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377 Research |
| title | USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377 |
| title_full | USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377 |
| title_fullStr | USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377 |
| title_full_unstemmed | USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377 |
| title_short | USP53 Drives Ethanol-Induced Myocardial Injury by Promoting K63 Deubiquitination-Dependent RIPK1 Activation at K377 |
| title_sort | usp53 drives ethanol induced myocardial injury by promoting k63 deubiquitination dependent ripk1 activation at k377 |
| url | https://spj.science.org/doi/10.34133/research.0823 |
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