YOD1 mediates isoproterenol-induced cardiac remodeling by deubiquitinating PKM2 and reducing PKM2 tetramerization in cardiomyocytes.

Heart failure, marked by rising morbidity and mortality rates, poses a significant health challenge. Recent studies suggest that deubiquitinating modification of proteins in cardiomyocytes is involved in the development of heart failure. YOD1 is a deubiquitinating enzyme (DUB) implicated in various diseases, including breast cancer, hematological tumors, pancreatic cancer, and vascular endothelial diseases. In this study, we investigated the role of YOD1 in the pathogenesis of cardiac hypertrophy. Mice were administered isoproterenol (ISO, 30 mg·kg(-1)·d(-1), through an osmotic pump) for two weeks to induce heart failure; neonatal murine ventricular myocytes were exposed to ISO (10 μM) for 24 h for in vitro studies. We showed that YOD1 expression levels were significantly upregulated in both in vitro and in vivo cardiac hypertrophy models. In cardiomyocyte-specific Yod1 knockout (YOD1CKO) mice, ISO-induced cardiac hypertrophy, fibrosis, and dysfunction were significantly ameliorated. We conducted quantitative proteomic screening and identified pyruvate kinase M2 (PKM2) as the substrate of YOD1 in cardiomyocytes. We then demonstrated that YOD1 directly bound to PKM2 and selectively cleaved K63-linked polyubiquitin chains from PKM2 at the K311 site through its active site H262, which subsequently disintegrated PKM2 tetramers and inhibited mitochondrial oxidative phosphorylation (OXPHOS) in cardiomyocytes. In ISO-treated cardiomyocytes, pretreatment with PKM2 activator TEPP-46 (20 μM) reversed YOD1 overexpression-induced hypertrophy and OXPHOS inhibition. This study reveals a new YOD1-PKM2 axis in cardiomyocytes and identifies YOD1 as a potential target for the treatment of ISO-induced cardiac remodeling and heart failure.