Cardiomyocyte USP20 alleviates septic cardiomyopathy by deubiquitinating and inhibiting NLRP3 activity

作者：Shanshan Dai, Yucong Zhang, Ziyi Huang, Yunxuan Chen, Zexin Yang, Ruihan Zheng, Kai Ye, Lingfeng Zhong, Xiangtao Zheng, Xueli Cai, Weijian Huang · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70494 · 被引用次数：3 · 研究领域：Ubiquitin and proteasome pathways、Peptidase Inhibition and Analysis、interferon and immune responses

OBJECTIVES: Although extensive research on septic cardiomyopathy has been conducted, effective therapies are still limited. Ubiquitin-specific peptidase 20 (USP20), a deubiquitinating enzyme, is critical in regulating protein ubiquitination and various cellular processes. whether USP20 is involved in the pathogenesis of septic cardiomyopathy remains unclear. This study investigated the impact of USP20 on septic cardiomyopathy. METHODS: The cardiomyocyte-specific USP20 knockout mice (USP20CKO) and NLRP3 knockout mice (NLRP3-/-) were used in the present study. A sepsis mouse model was established using lipopolysaccharide (LPS) administration and the cecal ligation and puncture (CLP) procedure. Recombinant adeno-associated virus serotype 9 (AAV9) was used to achieve overexpression of USP20. Myocardial function, histopathological changes, and pyroptosis levels in heart tissues were evaluated. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and co-immunoprecipitation (co-IP) were performed to identify the molecular mechanism of USP20 in septic cardiomyopathy. RESULTS: Our results showed that USP20 was downregulated in the myocardium of septic mice. Cardiomyocyte-specific USP20 deficiency worsened myocardial injury and cardiac dysfunction induced by LPS and CLP. LC-MS/MS analysis and co-IP revealed NLRP3 as a substrate protein of USP20. Mechanistically, USP20 removed K63-linked ubiquitin from K243 via its active site C154, inhibiting NLRP3's interaction with ASC ...