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

Author

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  • Jun Li

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Changming Li

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    East Hospital, Tongji University)

  • Dasheng Zhang

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Dan Shi

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Man Qi

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    East Hospital, Tongji University)

  • Jing Feng

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    East Hospital, Tongji University)

  • Tianyou Yuan

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Xinran Xu

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Dandan Liang

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Liang Xu

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Hong Zhang

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Yi Liu

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University)

  • Jinjin Chen

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    East Hospital, Tongji University)

  • Jiangchuan Ye

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    East Hospital, Tongji University)

  • 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
    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
    Institute of Medical Genetics, Tongji University
    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
    Laboratory of Hypoxic Cardiovascular Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Yi-Han Chen

    (Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine
    Institute of Medical Genetics, Tongji University
    East Hospital, Tongji University
    Tongji University School of Medicine)

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.

Suggested Citation

  • 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 C, 2014. "SNX13 reduction mediates heart failure through degradative sorting of apoptosis repressor with caspase recruitment domain," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6177
    DOI: 10.1038/ncomms6177
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    Cited by:

    1. Jian Huang & Luxin Wang & Yunli Shen & Shengqi Zhang & Yaqun Zhou & Jimin Du & Xiue Ma & Yi Liu & Dandan Liang & Dan Shi & Honghui Ma & Li Li & Qi Zhang & Yi-Han Chen, 2022. "CDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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