Luo Yue, Li Wei-Xin, Zheng Qing-Song, Yan Jue-Qian, Yang Yu-Die, Shen Si-Rui, Zhang Qian-Hui, Liang Guang, Wang Yi, Chen Ding-Dao, Hu Xiang, Luo Wu
The Affiliated Cangnan Hospital and Chemical Biology Research Center, Wenzhou Medical University, Wenzhou, 325800, China.
Medical Research Center, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China.
Acta Pharmacol Sin. 2025 May 20. doi: 10.1038/s41401-025-01567-x.
Myocardial infarction (MI) is an important risk factor of cardiovascular disease (CVD) and its incidence has been on the rise globally. Myocardial ischemia/reperfusion (I/R) injury is frequently detected in the ischemic myocardium. Recent studies have shown that ubiquitination plays an important role in the cardiac pathophysiological processes. Herein, we investigated the role and molecular mechanism of Ovarian tumor deubiquitinase 1 (OTUD1) in I/R induced myocardial injury. It was observed that the myocardial OTUD1 was upregulated in I/R-induced heart tissues and global deletion of OTUD1 significantly ameliorated I/R induced myocardial injury and dysfunction. Similarly, silencing or overexpression OTUD1 affected the hypoxia/reoxygenation (H/R) induced cell apoptosis in cultured cardiomyocytes. Mechanistically, immunoprecipitation-mass spectrometry revealed that OTUD1 directly bound to receptor for activated C-kinase 1 (RACK1) which has been identified as a scaffold protein for multiple kinases including mitogen-activated protein kinase (MAPKs) and Inhibitor of nuclear factor kappa B kinase (IKK). OTUD1 could cleave K63-linked polyubiquitin chains to enhance RACK1 phosphorylation, thus modulating MAPKs and nuclear factor kappa B (NF-κB) signaling. Finally, silencing of RACK1 reverses OTUD1-promoted H/R induced myocardial apoptosis. In conclusion, our findings suggest that OTUD1 promotes I/R-induced heart injury by deubiquitinating RACK1, suggesting that OTUD1 is a potential therapeutic target for myocardial I/R.
心肌梗死（MI）是心血管疾病（CVD）的一个重要危险因素，其发病率在全球范围内呈上升趋势。在缺血心肌中经常检测到心肌缺血/再灌注（I/R）损伤。最近的研究表明，泛素化在心脏病理生理过程中起重要作用。在此，我们研究了卵巢肿瘤去泛素化酶1（OTUD1）在I/R诱导的心肌损伤中的作用及分子机制。观察到在I/R诱导的心脏组织中心肌OTUD1上调，OTUD1的整体缺失显著改善了I/R诱导的心肌损伤和功能障碍。同样，沉默或过表达OTUD1影响培养心肌细胞中缺氧/复氧（H/R）诱导的细胞凋亡。机制上，免疫沉淀-质谱分析显示OTUD1直接与活化C激酶1受体（RACK1）结合，RACK1已被确定为包括丝裂原活化蛋白激酶（MAPKs）和核因子κB激酶抑制剂（IKK）在内的多种激酶的支架蛋白。OTUD1可以切割K63连接的多聚泛素链以增强RACK1磷酸化，从而调节MAPKs和核因子κB（NF-κB）信号通路。最后，沉默RACK1可逆转OTUD1促进的H/R诱导的心肌细胞凋亡。总之，我们的研究结果表明OTUD1通过去泛素化RACK1促进I/R诱导的心脏损伤，提示OTUD1是心肌I/R的潜在治疗靶点。
