title: SNX13 reduction mediates heart failure through degradative sorting of apoptosis repressor with caspase recruitment domain.
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.
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Changming
authors.initials: C
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Dasheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Man
authors.initials: M
authors.lastname: Qi
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.affiliation: 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.
authors.forename: Tianyou
authors.initials: T
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Xinran
authors.initials: X
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jiangchuan
authors.initials: J
authors.lastname: Ye
authors.affiliation: Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Weifang
authors.initials: W
authors.lastname: Jiang
authors.affiliation: 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 Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Cardiothoracic Surgical Department, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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 [3] Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Luying
authors.initials: L
authors.lastname: Peng
authors.affiliation: 1] Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China [2] Laboratory of Hypoxic Cardiovascular Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhaonian
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: 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 [3] Department of Cardiology, East Hospital, Tongji University, Shanghai 200120, China [4] Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D058305:Sorting Nexins / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D051017:Apoptosis Regulatory Proteins; D009124:Muscle Proteins; C112246:NOL3 protein, human; C491787:Nol3 protein, mouse; C442319:SNX13 protein, human; D058305:Sorting Nexins; D053181:Caspase 8