Abstract 12936: A Critical Role of Deubiquitinase OTUB1 in Adaptive Cardiac Hypertrophy

Abstract

Ubiquitin-mediated proteolysis is essential for protein homeostasis, and its defects lead to the development of various cardiomyopathies and heart failure. By reversing the ubiquitination and degradation of target proteins, deubiquitinases (DUBs) play a crucial role in protein homeostasis. However, the importance of DUBs in cardiac pathophysiology is largely unknown. Here we addressed the role of the DUB OTU domain aldehyde binding-1 (OTUB1) in the heart. Bioinformatics analysis reveals an upregulation of OTUB1 in hypertrophic and failing human hearts. In cultured cardiomyocytes, adrenergic agonists induced upregulation and activation of OTUB1. Silencing OTUB1 in repressed adrenergic agonists-induced fetal gene re-activation, protein synthesis and cardiomyocyte hypertrophy. In vivo , mice deficient of OTUB1 in the heart developed dilated cardiomyopathy and heart failure, leading to premature lethality. The severe cardiac phenotype is accompanied by lipid accumulation, ER dilatation, prevalent autophagic vesicles containing ribosomes, as well as dysregulated expression of metabolic and ribosome genes. Delivery of wild-type OTUB1, but not the enzymatic dead mutant, via AAV9 to OTUB1-deficient hearts attenuated cardiac dysfunction and prolonged the lifespan of mice. Mechanistically, loss of OTUB1 suppressed the degradation of Deptor, an inhibitory mTOR regulator, leading to impaired mTOR signaling in cultured cardiomyocytes and mouse hearts. Collectively, these findings suggest OTUB1 is required for physiological cardiac growth by fine-tuning mTOR signaling and identify OTUB1 as a novel regulator of cardiac homeostasis.