Cardiomyocyte-derived OTUD7B promotes cardiac hypertrophy by deubiquitinating SERCA2a.

Abstract

Pathological cardiac hypertrophy, triggered by persistent neurohumoral or hemodynamic stress, is a key precursor of ventricular dysfunction and heart failure. Deubiquitinating enzymes (DUBs) have emerged as critical regulators of cardiovascular biology. This study examined the function of a DUB, ovarian tumor domain-containing 7B (OTUD7B), in cardiac hypertrophy.Cardiomyocyte-specific OTUD7B knockout and overexpression mouse models were generated to evaluate myocardial hypertrophy and cardiac dysfunction in response to angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Quantitative ubiquitinome analysis, site-directed mutagenesis, and co-immunoprecipitation assays were performed to explore the substrate and mechanism of OTUD7B.Transcriptomic and experimental validation demonstrated that cardiomyocyte OTUD7B was increased in hypertrophic hearts of both humans and mice. Cardiomyocyte-specific deletion of OTUD7B significantly mitigated angiotensin II (Ang II)- and transverse aortic constriction (TAC)-induced cardiac hypertrophy and dysfunction in mice. Mechanistically, quantitative ubiquitinome analysis identified sarcoplasmic/endoplasmic reticulum CaATPase 2a (SERCA2a) as a direct substrate of OTUD7B. OTUD7B bound to SERCA2a and removed K63-linked ubiquitin at K628 through its catalytic site C194. This deubiquitination promoted SERCA2a-phospholamban (PLN) interaction, thereby restricting SERCA2a activity in Ca²⁺ handling and driving hypertrophic response in cardiomyocytes. Moreover, cardiomyocyte-specific OTUD7B overexpression exacerbated TAC-induced cardiac hypertrophy and dysfunction by deubiquitinating SERCA2a at K628.This study defines a novel OTUD7B-SERCA2a regulatory axis and identifies OTUD7B as a promising therapeutic target for cardiac hypertrophy and dysfunction.