1] Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Institute of Medical Genetics, Tongji University, Shanghai 200092, China.
1] Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Department of Cardiology, East Hospital, Tongji University, Shanghai 200120, China.
Nat Commun. 2014 Oct 8;5:5177. doi: 10.1038/ncomms6177.
Heart failure (HF) is associated with complicated molecular remodelling within cardiomyocytes; however, the mechanisms underlying this process remain unclear. Here we show that sorting nexin-13 (SNX13), a member of both the sorting nexin and the regulator of G protein signalling (RGS) protein families, is a potent mediator of HF. Decreased levels of SNX13 are observed in failing hearts of humans and of experimental animals. SNX13-deficient zebrafish recapitulate HF with striking cardiomyocyte apoptosis. Mechanistically, a reduction in SNX13 expression facilitates the degradative sorting of apoptosis repressor with caspase recruitment domain (ARC), which is a multifunctional inhibitor of apoptosis. Consequently, the apoptotic pathway is activated, resulting in the loss of cardiac cells and the dampening of cardiac function. The N-terminal PXA structure of SNX13 is responsible for mediating the endosomal trafficking of ARC. Thus, this study reveals that SNX13 profoundly affects cardiac performance through the SNX13-PXA-ARC-caspase signalling pathway.
心力衰竭（HF）与心肌细胞内复杂的分子重塑有关；然而，这一过程的机制仍不清楚。在这里，我们表明分选连接蛋白 13（SNX13）是分选连接蛋白和 G 蛋白信号调节因子（RGS）蛋白家族的成员，是心力衰竭的有力介质。在人和实验动物的衰竭心脏中观察到 SNX13 水平降低。SNX13 缺陷的斑马鱼重现了具有明显心肌细胞凋亡的心力衰竭。从机制上讲，SNX13 表达的减少促进了具有半胱天冬酶募集结构域（ARC）的凋亡抑制剂的降解性分选，ARC 是一种多功能凋亡抑制剂。因此，凋亡途径被激活，导致心脏细胞的丧失和心脏功能的减弱。SNX13 的 N 端 PXA 结构负责介导 ARC 的内体运输。因此，这项研究表明，SNX13 通过 SNX13-PXA-ARC-半胱天冬酶信号通路对心脏功能产生深远影响。
