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. 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. 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.

中文翻译：

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去泛素化酶 OTUD6a 通过 STING 去泛素化驱动心脏炎症和肥大

心脏肥大是高血压性心脏病和随后的心力衰竭的重要病理特征。已发现去泛素化酶（DUB）参与心肌肥大的调节。含 OTU 结构域的蛋白 6a (OTUD6a) 是最近鉴定的 DUB。迄今为止，OTUD6a 在心肌肥厚中的潜在作用尚未被揭示。我们检测了小鼠或人类肥厚心脏组织中 OTUD6a 水平的上调。然后，在 OTUD6a 基因敲除小鼠 (OTUD6a) 中，横主动脉缩窄 (TAC) 或血管紧张素 II (Ang II) 诱导的心室肥厚和功能障碍显着减弱。在机制上，我们通过免疫沉淀分析和质谱鉴定，干扰素基因刺激剂（STING）是OTUD6a的直接底物蛋白。OTUD6a 通过清除心肌细胞中 K48 连接的泛素来维持 STING 稳定性。随后，OTUD6a 在体内和体外调节 STING 下游 NF-κB 信号传导激活和炎症基因表达。抑制 STING 可阻断 OTUD6a 过表达诱导的心肌细胞炎症和肥大反应。这一发现扩展了我们对 OTUD6a 在心肌肥大中有害作用的理解，并将 STING 确定为 OTUD6a 的去泛素化底物，表明靶向 OTUD6a 可能是治疗心脏肥大的潜在策略。