The deubiquitinase OTUD6B regulates cardiac hypertrophy by stabilizing TNF receptor associated factor 2

Pathological cardiac hypertrophy serves as the primary pathological driver of heart failure, significantly impacting patient prognosis. Deubiquitinating enzymes, which play pivotal roles in protein homeostasis, are emerging as key regulators in cardiac hypertrophy and dysfunction. This study sought to elucidate the contribution of a specific deubiquitinase, Ovarian tumor (OTU) Domain-Containing Deubiquitinase 6B‌ (OTUD6B), to cardiac hypertrophy and explore its functional mechanisms.

A mouse model of pressure overload cardiac hypertrophy was established through transverse aortic constriction (TAC) surgery for 8 weeks, and phenylephrine (PE) stimulated hypertrophic responses in cardiomyocyte cultures. Cardiac function and morphology were analyzed via echocardiography and histology. To explore underlying mechanisms, we used molecular docking, immunofluorescence co-localization, co-IP, and in vivo ubiquitination assays.

OTUD6B was highly expressed in humans and mice with hypertrophy-associated heart failure (HF). Knocking down OTUD6B reduced cardiomyocyte enlargement in both cellular and TAC-induced mouse models, whereas its overexpression worsened cardiac hypertrophy. OTUD6B physically bound TNF receptor associated factor 2 (TRAF2) and enhanced its stability by removing K48-linked polyubiquitin chains. Notably, cardiomyocyte-specific TRAF2 downregulation in the heart markedly reduced OTUD6B's hypertrophic-promoting effect in vivo.

These findings suggest that OTUD6B positively regulates cardiac hypertrophy by stabilizing TRAF2 and identify OTUD6B as a target for hypertrophic therapy.