Zhao Tingting, Bai Yangjinming, Fei Yudong, Wei Zhixing, Yao Pengcheng, Che Qianji, Zhang Yichao, Yan Ji, Chen Kaiyan, Wu Zhengyang, Qiu Junhao, Wang Yuepeng, Li Wei, Wang Qian, Li Yigang
Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
iScience. 2025 Aug 6;28(9):113302. doi: 10.1016/j.isci.2025.113302. eCollection 2025 Sep 19.
CPNE5, a member of the Copine family, is characterized by its membrane-binding properties and functions as a regulatory modulator of intracellular signaling through the spatial redistribution of interacting protein partners. Emerging evidence has demonstrated that CPNE3 exerts cardioprotective effects via anti-apoptotic activity in myocardial ischemia-reperfusion injury models. However, the functional role of CPNE5 in cardiac pathology remains unclear. In this study, the cardiac-specific overexpression of CPNE5 in mice improved cardiac function, reduced cellular apoptosis, and attenuated cardiac fibrosis in both transverse aortic constriction and ischemia-reperfusion models. Conversely, CPNE5 knockout mice exhibited opposite pathological phenotypes. Mechanistic studies revealed that CPNE5 retains FAS within the endoplasmic reticulum and promotes its degradation through the ER-phagy pathway. This process involves CPNE5's interaction with the autophagy marker LC3 and CALCOCO1, a key receptor in the ER-lysosome-associated degradation (ERLAD) pathway. Collectively, these findings indicate that CPNE5 overexpression protects cardiomyocytes against FASL-induced apoptosis under stress and ischemic conditions.
CPNE5是Copine家族的成员之一，其特点是具有膜结合特性，并通过相互作用的蛋白质伙伴的空间重新分布，作为细胞内信号传导的调节调节剂发挥作用。新出现的证据表明，在心肌缺血-再灌注损伤模型中，CPNE3通过抗凋亡活性发挥心脏保护作用。然而，CPNE5在心脏病理中的功能作用仍不清楚。在本研究中，在小鼠中特异性过表达CPNE5可改善心脏功能，减少细胞凋亡，并减轻横向主动脉缩窄和缺血-再灌注模型中的心脏纤维化。相反，CPNE5基因敲除小鼠表现出相反的病理表型。机制研究表明，CPNE5将FAS保留在内质网中，并通过内质网自噬途径促进其降解。这个过程涉及CPNE5与自噬标记物LC3和CALCOCO1的相互作用，CALCOCO1是内质网-溶酶体相关降解（ERLAD）途径中的关键受体。总的来说，这些发现表明，CPNE5过表达可在应激和缺血条件下保护心肌细胞免受FASL诱导的凋亡。
