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CDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation

Author

Listed:
  • Jian Huang

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University)

  • Luxin Wang

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University)

  • Yunli Shen

    (Tongji University School of Medicine
    Tongji University School of Medicine)

  • Shengqi Zhang

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University)

  • Yaqun Zhou

    (Tongji University School of Medicine)

  • Jimin Du

    (Tongji University School of Medicine)

  • Xiue Ma

    (Tongji University School of Medicine
    Tongji University)

  • Yi Liu

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University)

  • Dandan Liang

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University)

  • Dan Shi

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University)

  • Honghui Ma

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University
    Chinese Academy of Medical Sciences)

  • Li Li

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University
    Chinese Academy of Medical Sciences)

  • Qi Zhang

    (Tongji University School of Medicine
    Tongji University School of Medicine)

  • Yi-Han Chen

    (Tongji University School of Medicine
    Tongji University School of Medicine
    Tongji University
    Tongji University School of Medicine)

Abstract

Kinase-catalyzed phosphorylation plays a crucial role in pathological cardiac hypertrophy. Here, we show that CDC-like kinase 4 (CLK4) is a critical regulator of cardiomyocyte hypertrophy and heart failure. Knockdown of Clk4 leads to pathological cardiomyocyte hypertrophy, while overexpression of Clk4 confers resistance to phenylephrine-induced cardiomyocyte hypertrophy. Cardiac-specific Clk4-knockout mice manifest pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Further investigation identifies nexilin (NEXN) as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN is sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring phosphorylation of NEXN ameliorates myocardial hypertrophy in mice with cardiac-specific Clk4 deletion. We conclude that CLK4 regulates cardiac function through phosphorylation of NEXN, and its deficiency may lead to pathological cardiac hypertrophy. CLK4 is a potential intervention target for the prevention and treatment of heart failure.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31996-9
    DOI: 10.1038/s41467-022-31996-9
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    References listed on IDEAS

    as
    1. Eleni Petsalaki & George Zachos, 2016. "Clks 1, 2 and 4 prevent chromatin breakage by regulating the Aurora B-dependent abscission checkpoint," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
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