Abstract

Deubiquitinases (DUBs), a family enzymes that reverse the process of ubiquitination, participate in diverse cellular processes through regulating protein degradation, intracellular trafficking, cell signaling, and protein‐protein interaction. The functional importance of DUBs in cardiac pathophysiology remains poorly defined. Herein, we report a critical role of OTUB1, one of the most highly expressed DUBs in the heart, in adaptive cardiac remodeling. Analysis of RNA sequencing data revealed that OTUB1 is upregulated in the failing human hearts. OTUB1 is also upregulated and activated in cardiomyocytes (CMs) treated with adrenergic agonists. OTUB1‐deficient CMs were resistant to phenylephrine (PE) ‐ and isoproterenol‐induced CM hypertrophy as characterized by attenuated cell enlargement, decreased fetal gene activation, and diminished protein synthesis. In vivo, CM‐specific deletion of OTUB1 in the developing mouse heart caused dilated cardiomyopathy without a prior development of compensatory cardiac hypertrophy, eventually leading to heart failure and premature lethality of mice by 6 months of age. 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. On the molecular level, OTUB1 deficiency blunted mTOR signaling in cultured CMs and mouse hearts. Our findings indicate that OTUB1 is indispensable for the development of adaptive cardiac hypertrophy, possibly through modulating mTOR signaling.

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