SNX13 reduction mediates heart failure through degradative sorting of apoptosis repressor with caspase recruitment domain

Jun Li, Changming Li, Dasheng Zhang, Dan Shi, Man Qi, Jing Feng, Tianyou Yuan, Xinran Xu, Dandan Liang, Liang Xu, Hong Zhang, Yi Liu, Jinjin Chen, Jiangchuan Ye, Weifang Jiang, Yingyu Cui, Yangyang Zhang, Luying Peng, Zhaonian Zhou and Yi-Han Chen ()
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Jun Li: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Changming Li: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Dasheng Zhang: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Dan Shi: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Man Qi: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Jing Feng: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Tianyou Yuan: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Xinran Xu: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Dandan Liang: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Liang Xu: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Hong Zhang: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Yi Liu: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Jinjin Chen: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Jiangchuan Ye: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Weifang Jiang: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Yingyu Cui: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Yangyang Zhang: the First Affiliated Hospital of Nanjing Medical University
Luying Peng: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Zhaonian Zhou: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
Yi-Han Chen: Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms6177

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