OTUD1 aggravates pathological cardiac hypertrophy through activation of PGAM5-ASK1 signaling pathways

Deubiquitinating enzymes have gained more and more attention in the field of pathological cardiac hypertrophy. In this study, we explored the role of a deubiquitinase, OTUD1, in the transverse aortic constriction (TAC) induced cardiac hypertrophy. We found the upregulation of OTUD1 in heart tissues of TAC mice. OTUD1 overexpression promoted cardiac hypertrophy, cardiac fibrosis and apoptosis. Conversely, OTUD1 depletion alleviated these pathological changes both in vivo and in vitro. Mechanistically, ASK1 was identified as one substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. Interestingly, OTUD1 didn’t deubiquitinate ASK1, but increased the phosphorylation level of ASK1 during the process of cardiac hypertrophy. We found that PGAM5, the upper stream regulator of ASK1, was stabilized by OTUD1 in a K63 ubiquitin chain dependent way, which reminded us OTUD1 increased the phosphorylation level of ASK1 by deubiquitinating PGAM5. This study identified the OTUD1-ASK1 axis as a potential therapeutic target for pathological cardiac hypertrophy.去泛素化酶（deubiquitinating enzymes）在病理性心肌肥厚领域日益受到关注。本研究探讨了去泛素化酶OTUD1在主动脉弓缩窄（transverse aortic constriction, TAC）诱导的心肌肥厚中的作用。我们在TAC模型小鼠的心肌组织中观察到OTUD1表达上调。OTUD1过表达可促进心肌肥厚、心肌纤维化与细胞凋亡；反之，敲低OTUD1则可在体内及体外实验中减轻上述病理变化。从机制角度而言，我们通过免疫共沉淀联合液相色谱-串联质谱（LC-MS/MS）鉴定出ASK1为OTUD1的底物之一。值得注意的是，OTUD1并未直接对ASK1进行去泛素化修饰，而是在心肌肥厚进程中提升了ASK1的磷酸化水平。我们进一步发现，ASK1的上游调控因子磷酸甘油酸变位酶5（PGAM5）可通过OTUD1以K63泛素链（K63 ubiquitin chain）依赖的方式被稳定，这提示OTUD1可通过对PGAM5进行去泛素化修饰，进而提升ASK1的磷酸化水平。本研究证实OTUD1-ASK1轴可作为病理性心肌肥厚的潜在治疗靶点。