Background
Cardiac hypertrophy is a crucial pathological characteristic of hypertensive heart disease and subsequent heart failure. Deubiquitinating enzymes (DUBs) have been found to be involved in the regulation of myocardial hypertrophy. OTU Domain-Containing Protein 6a (OTUD6a) is a recently identified DUB. To date, the potential role of OTUD6a in myocardial hypertrophy has not yet been revealed.
Conclusion
This finding extends our understanding of the detrimental role of OTUD6a in myocardial hypertrophy and identifies STING as a deubiquinating substrate of OTUD6a, indicating that targeting OTUD6a could be a potential strategy for the treatment of cardiac hypertrophy.
Results
We examined the up-regulated level of OTUD6a in mouse or human hypertrophic heart tissues. Then, transverse aortic constriction (TAC)- or angiotensin II (Ang II)- induced ventricular hypertrophy and dysfunction were significantly attenuated in OTUD6a gene knockout mice (OTUD6a-/-). In mechanism, we identified that the Stimulator of Interferon Genes (STING) is a direct substrate protein of OTUD6a via immunoprecipitation assay and mass spectrometry. OTUD6a maintains STING stability via clearing the K48-linked ubiquitin in cardiomyocytes. Subsequently, OTUD6a regulates the STING-downstream NF-κB signaling activation and inflammatory gene expression both in vivo and in vitro. Inhibition of STING blocked OTUD6a overexpression-induced inflammatory and hypertrophic responses in cardiomyocytes.