Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
Nat Cardiovasc Res. 2023 Aug;2(8):764-777. doi: 10.1038/s44161-023-00313-y. Epub 2023 Aug 7.
Cardiac hypertrophy leads to myocardial dysfunction and represents a serious threat to global public health security. Deubiquitinating enzymes (DUBs) mainly maintain the stability of substrate proteins and are essential to cardiac pathophysiology. Here, we explored the role and regulating mechanism of a DUB, Josephin domain-containing protein 2 (JOSD2), in cardiac hypertrophy. We found that JOSD2 expression was significantly upregulated in hypertrophic myocardium. Josd2 gene knockout aggravated cardiac dysfunction and hypertrophy in mice, whereas cardiac overexpression of JOSD2 mediated by the AAV9 vector prevented angiotensin II-induced cardiac hypertrophy. A comprehensive proteome-wide quantitative analysis identified sarco/endoplasmic reticulum calcium ATPase 2a (SERCA2a) as a key substrate of JOSD2. Mechanistically, JOSD2 mediates SERCA2a deubiquitination, enhancing the stability of SERCA2a. By regulating SERCA2a, JOSD2 deficiency impairs calcium handling and promotes hypertrophy in primary cardiomyocytes. Our findings highlight the promise of JOSD2 as a beneficial therapeutic target for hypertrophic cardiomyopathy and provide an additional strategy for SERCA2a-targeted therapy.
心肌肥厚导致心肌功能障碍，严重威胁全球公共卫生安全。去泛素化酶（DUBs）主要维持底物蛋白的稳定性，对心脏病理生理学至关重要。在这里，我们探讨了一种 DUB，即 Josephin 结构域蛋白 2（JOSD2）在心肌肥厚中的作用和调节机制。我们发现 JOSD2 在肥厚心肌中的表达显著上调。Josd2 基因敲除加剧了小鼠的心脏功能障碍和肥大，而通过 AAV9 载体过表达 JOSD2 可预防血管紧张素 II 诱导的心脏肥大。全面的蛋白质组定量分析确定肌浆/内质网钙 ATP 酶 2a（SERCA2a）是 JOSD2 的关键底物。从机制上讲，JOSD2 介导 SERCA2a 的去泛素化，增强 SERCA2a 的稳定性。通过调节 SERCA2a，JOSD2 缺乏会损害钙处理并促进原代心肌细胞肥大。我们的研究结果强调了 JOSD2 作为肥厚性心肌病有益治疗靶点的潜力，并为 SERCA2a 靶向治疗提供了另一种策略。
