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

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 () and Yi-Han Chen ()
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Jian Huang: Tongji University School of Medicine
Luxin Wang: Tongji University School of Medicine
Yunli Shen: Tongji University School of Medicine
Shengqi Zhang: Tongji University School of Medicine
Yaqun Zhou: Tongji University School of Medicine
Jimin Du: Tongji University School of Medicine
Xiue Ma: Tongji University School of Medicine
Yi Liu: Tongji University School of Medicine
Dandan Liang: Tongji University School of Medicine
Dan Shi: Tongji University School of Medicine
Honghui Ma: Tongji University School of Medicine
Li Li: Tongji University School of Medicine
Qi Zhang: Tongji University School of Medicine
Yi-Han Chen: Tongji University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31996-9

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