Coupling of USP10 de-ubiquitination and chaperone-mediated autophagy causes cardiac sodium channel degradation and cardiac arrhythmias

作者：Hongbo Xiong, Di Guo, Zhen Zhou, Lilin Xiang, Xiangjie Kong, Tong Zhang, Zhijie Wang, Huanhuan Cai, Di Fan, Qiongxin Wang, Qiongxin Wang, Yimei Du, Qing K Wang, Qing Wang, Zhibing Lu · 发表于：Cardiovascular Research · 年份：2025 · DOI：10.1093/cvr/cvaf214 · 被引用次数：2 · 研究领域：Heat shock proteins research、Cardiac electrophysiology and arrhythmias、Autophagy in Disease and Therapy

AIMS: SCN5A encodes cardiac sodium channel Nav1.5 that maintains normal electrophysiological functions of hearts. Loss-of-function variants of Nav1.5 reduce sodium current densities (INa) and cause arrhythmias such as cardiac conduction block or Brugada syndrome. The regulatory mechanisms of Nav1.5 functions are not fully understood. The aim of this study was to identify novel proteins that interact with Nav1.5 and characterize their regulatory mechanisms on Nav1.5 and arrhythmias. METHODS AND RESULTS: GST pull-down coupled with mass spectrometry, co-immunoprecipitation, and mutational analysis were used to identify de-ubiquitinating enzyme USP10 as a novel Nav1.5-interacting protein, and showed that USP10 reduces Nav1.5 protein expression and INa densities in vitro. AAV9-mediated cardiac overexpression of USP10 in mice reduced Nav1.5 protein expression, INa and ICa-L densities, shortened APD, and caused delayed ventricular activation, spontaneous atrioventricular conduction block, sinus pause, and ventricular tachycardia induced with electrical pacing. Cardiac knockdown of USP10 in Scn5a+/- mice restored Nav1.5, INa, and ICa-L to levels comparable to wild-type mice, and alleviated the conduction delay and premature ventricular contractions. Mechanistically, USP10 increased Nav1.5 protein degradation through chaperone-mediated autophagy (CMA) as the effect was blocked by lysosome inhibitor CQ and inhibition of CMA using siRNA targeting LAMP2A or HSC70, but not by proteasomal ...