The Deubiquitinase OTUD5 regulates cardiac hypertrophy by stabilizing TNF receptor associated factor 2.

BACKGROUND

Pathological cardiac hypertrophy acts as a major pathological contributor to heart failure, profoundly influencing patient outcomes. Deubiquitinating enzymes, which are critical for maintaining protein homeostasis, are increasingly recognized as essential regulators in cardiac hypertrophy and dysfunction. This study aimed to investigate the role of a specific deubiquitinase, Ovarian tumor domain-containing protein 5 (OTUD5), in cardiac hypertrophy and elucidate its functional mechanisms.

METHODS

A pressure overload-induced cardiac hypertrophy model was created in mice using transverse aortic constriction (TAC) surgery. Additionally, phenylephrine (PE) was employed to induce hypertrophic responses in cultured cardiomyocytes. Cardiac function and structural changes were assessed through echocardiography and histological analysis. To uncover the underlying mechanisms, techniques such as molecular docking, immunofluorescence co-localization, co-immunoprecipitation (co-IP), and in vivo ubiquitination assays were utilized.

RESULTS

OTUD5 exhibited elevated expression in both human and mouse samples with hypertrophy-associated heart failure (HF). Silencing OTUD5 diminished cardiomyocyte enlargement in both cellular and TAC-induced mouse models, whereas its overexpression exacerbated cardiac hypertrophy. Mechanically, OTUD5 physically interacted with TNF receptor-associated factor 2 (TRAF2) and bolstered its stability by cleaving K48-linked polyubiquitin chains. Furthermore, OTUD5 activates the NF-κB and AKT/GSK3β signaling pathways in TRAF2-dependent manner. Importantly, cardiomyocyte-specific knockdown of TRAF2 in the heart significantly attenuated OTUD5's hypertrophic-promoting effects in vivo.

CONCLUSIONS

These findings indicate that OTUD5 positively modulates cardiac hypertrophy by stabilizing TRAF2 and promote activation of NF-κB and AKT/GSK3β signaling, positioning OTUD5 as a potential therapeutic target for cardiac hypertrophy.