Deubiquitinase USP25 Alleviates Obesity-Induced Cardiac Remodeling and Dysfunction by Downregulating TAK1 and Reducing TAK1-Mediated Inflammation
Bozhi Ye, Yanghao Chen, Xudong Chen, Diyun Xu, Yucheng Jiang, Wante Lin, Danhong Fang, Jiachen Xu, Jibo Han, Xue Han, Xiaohong Long, Wei Wang, Hao Zhou, Gaojun Wu, Guang Liang
Abstract
Deubiquitinating enzymes play a vital role in cardiovascular diseases. This study found that cardiomyocyte ubiquitin-specific protease 25 (USP25) expression was downregulated both in myocardial tissue of obesity cardiomyopathy and palmitic acid-stimulated cardiomyocytes. USP25 deficiency exacerbated high-fat diet-induced ventricular remodeling in mice, whereas overexpression of USP25 in cardiomyocytes reversed this pathological phenotype. Mechanistically, USP25 directly binds to TAK1 and P62, and the 178-cysteine of USP25 removes the K63 ubiquitin chain from P62, which promotes the degradation of TAK1 through the autophagy-lysosome pathway, thereby ameliorating obesity-induced ventricular remodeling by reducing inflammation through the TAK1-MAPK pathway. This finding identifies USP25 as a potential therapeutic target for obesity cardiomyopathy.