Cardiomyocyte‐Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination
Abstract Although pathological cardiac hypertrophy is a key driver of heart failure, the underlying mechanisms remain incompletely elucidated. This study investigates the role and mechanism of deubiquitinating enzyme (DUB) ubiquitin‐specific protease 20 (USP20) in cardiac hypertrophy. Transcriptomic...
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202416478 |
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| author | Lingfeng Zhong Shanshan Dai Fan Yu Guo‐Ping Shi Qinyan Gong Yucong Zhang Jingsi Duan Zhengyin Lou Zhixuan Tang Fuzhe Gong Derong Chen Liya Hou Xinyang Hu Jinghai Chen Jian'an Wang Deling Yin |
| author_facet | Lingfeng Zhong Shanshan Dai Fan Yu Guo‐Ping Shi Qinyan Gong Yucong Zhang Jingsi Duan Zhengyin Lou Zhixuan Tang Fuzhe Gong Derong Chen Liya Hou Xinyang Hu Jinghai Chen Jian'an Wang Deling Yin |
| author_sort | Lingfeng Zhong |
| collection | DOAJ |
| description | Abstract Although pathological cardiac hypertrophy is a key driver of heart failure, the underlying mechanisms remain incompletely elucidated. This study investigates the role and mechanism of deubiquitinating enzyme (DUB) ubiquitin‐specific protease 20 (USP20) in cardiac hypertrophy. Transcriptomic profiling of hypertrophic hearts shows significant alterations in the expression of DUBs, including a remarkable downregulation of USP20. USP20 is predominantly expressed in cardiomyocytes. Co‐immunoprecipitation (Co‐IP) followed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) is used to identify USP20 substrates. Cleavage Under Targets and Tagmentation assay (CUT&Tag) sequencing is employed to identify downstream targets of signal transducer and activator of transcription 3 (STAT3). Functionally, USP20 deficiency exacerbates cardiac hypertrophy induced by either angiotensin II (Ang II) or transverse aortic constriction (TAC), whereas USP20 overexpression alleviates hypertrophic responses. Mechanistically, USP20 deubiquitinates STAT3 by removing K63‐linked ubiquitin chains at K177 via its H645 active site, reducing STAT3 phosphorylation and nuclear translocation. This inhibites STAT3's transcriptional activity at coactivator‐associated arginine methyltransfer (Carm1) promoter, leading to upregulated CARM1 expression and mitigated hypertrophy. Importantly, the STAT3 inhibitor Stattic confirms STAT3 serves as a key substrate mediating the cardiac protective effects of USP20. These findings unveil a novel USP20/STAT3/CARM1 axis in cardiomyocytes and reveal its therapeutic potential for cardiac hypertrophy. |
| format | Article |
| id | doaj-art-3ccdffc4b30b4c18b84f0a8f09ff7a2b |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-3ccdffc4b30b4c18b84f0a8f09ff7a2b2025-08-20T02:36:40ZengWileyAdvanced Science2198-38442025-06-011223n/an/a10.1002/advs.202416478Cardiomyocyte‐Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 DeubiquitinationLingfeng Zhong0Shanshan Dai1Fan Yu2Guo‐Ping Shi3Qinyan Gong4Yucong Zhang5Jingsi Duan6Zhengyin Lou7Zhixuan Tang8Fuzhe Gong9Derong Chen10Liya Hou11Xinyang Hu12Jinghai Chen13Jian'an Wang14Deling Yin15Department of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaThe Key Laboratory of Emergency and Disaster Medicine of Wenzhou Department of Emergency The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Medicine Brigham and Women's Hospital Harvard Medical School 77 Avenue Louis Pasteur, NRB‐7 Boston MA 02115 USADepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of First Affiliated Hospital of Wenzhou Medical University Wenzhou 325000 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaDepartment of Cardiology of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 ChinaAbstract Although pathological cardiac hypertrophy is a key driver of heart failure, the underlying mechanisms remain incompletely elucidated. This study investigates the role and mechanism of deubiquitinating enzyme (DUB) ubiquitin‐specific protease 20 (USP20) in cardiac hypertrophy. Transcriptomic profiling of hypertrophic hearts shows significant alterations in the expression of DUBs, including a remarkable downregulation of USP20. USP20 is predominantly expressed in cardiomyocytes. Co‐immunoprecipitation (Co‐IP) followed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) is used to identify USP20 substrates. Cleavage Under Targets and Tagmentation assay (CUT&Tag) sequencing is employed to identify downstream targets of signal transducer and activator of transcription 3 (STAT3). Functionally, USP20 deficiency exacerbates cardiac hypertrophy induced by either angiotensin II (Ang II) or transverse aortic constriction (TAC), whereas USP20 overexpression alleviates hypertrophic responses. Mechanistically, USP20 deubiquitinates STAT3 by removing K63‐linked ubiquitin chains at K177 via its H645 active site, reducing STAT3 phosphorylation and nuclear translocation. This inhibites STAT3's transcriptional activity at coactivator‐associated arginine methyltransfer (Carm1) promoter, leading to upregulated CARM1 expression and mitigated hypertrophy. Importantly, the STAT3 inhibitor Stattic confirms STAT3 serves as a key substrate mediating the cardiac protective effects of USP20. These findings unveil a novel USP20/STAT3/CARM1 axis in cardiomyocytes and reveal its therapeutic potential for cardiac hypertrophy.https://doi.org/10.1002/advs.202416478cardiac hypertrophycardiomyocytedeubiquitinating enzymesignal transducer and activator of transcription 3ubiquitin‐specific protease 20 |
| spellingShingle | Lingfeng Zhong Shanshan Dai Fan Yu Guo‐Ping Shi Qinyan Gong Yucong Zhang Jingsi Duan Zhengyin Lou Zhixuan Tang Fuzhe Gong Derong Chen Liya Hou Xinyang Hu Jinghai Chen Jian'an Wang Deling Yin Cardiomyocyte‐Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination Advanced Science cardiac hypertrophy cardiomyocyte deubiquitinating enzyme signal transducer and activator of transcription 3 ubiquitin‐specific protease 20 |
| title | Cardiomyocyte‐Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination |
| title_full | Cardiomyocyte‐Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination |
| title_fullStr | Cardiomyocyte‐Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination |
| title_full_unstemmed | Cardiomyocyte‐Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination |
| title_short | Cardiomyocyte‐Enriched USP20 Ameliorates Pathological Cardiac Hypertrophy by Targeting STAT3 Deubiquitination |
| title_sort | cardiomyocyte enriched usp20 ameliorates pathological cardiac hypertrophy by targeting stat3 deubiquitination |
| topic | cardiac hypertrophy cardiomyocyte deubiquitinating enzyme signal transducer and activator of transcription 3 ubiquitin‐specific protease 20 |
| url | https://doi.org/10.1002/advs.202416478 |
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