Dysregulated RBM24 phosphorylation impairs APOE translation underlying psychological stress-induced cardiovascular disease

He Yang, Lei Sun, Xuemei Bai, Bingcheng Cai, Zepeng Tu, Chen Fang, Yusheng Bian, Xiaoyu Zhang, Xudong Han, Dayin Lv, Chi Zhang, Bo Li, Shaoxiang Luo, Bingbing Du, Lan Li, Yufeng Yao, Zhiqiang Dong, Zhuowei Huang, Guanhua Su, Hui Li (), Qing K. Wang () and Min Zhang ()
Additional contact information
He Yang: Huazhong Agricultural University
Lei Sun: Huazhong Agricultural University
Xuemei Bai: Huazhong University of Science and Technology
Bingcheng Cai: Huazhong Agricultural University
Zepeng Tu: Huazhong Agricultural University
Chen Fang: Huazhong University of Science and Technology
Yusheng Bian: Huazhong Agricultural University
Xiaoyu Zhang: Huazhong University of Science and Technology
Xudong Han: Huazhong Agricultural University
Dayin Lv: Huazhong University of Science and Technology
Chi Zhang: Huazhong University of Science and Technology
Bo Li: Huazhong Agricultural University
Shaoxiang Luo: Ltd
Bingbing Du: Huazhong Agricultural University
Lan Li: Huazhong Agricultural University
Yufeng Yao: Huazhong University of Science and Technology
Zhiqiang Dong: Huazhong Agricultural University
Zhuowei Huang: Huazhong University of Science and Technology
Guanhua Su: Huazhong University of Science and Technology
Hui Li: Huazhong University of Science and Technology
Qing K. Wang: Huazhong University of Science and Technology
Min Zhang: Huazhong Agricultural University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Psychological stress contributes to cardiovascular disease (CVD) and sudden cardiac death, yet its molecular basis remains obscure. RNA binding protein RBM24 plays a critical role in cardiac development, rhythm regulation, and cellular stress. Here, we show that psychological stress activates RBM24 S181 phosphorylation through eIF4E2-GSK3β signaling, which causally links psychological stress to CVD by promoting APOE translation (apolipoprotein E). Using an Rbm24 S181A KI mouse model, we show that impaired S181 phosphorylation leads to cardiac contractile dysfunction, atrial fibrillation, dyslipidemia, reduced muscle strength, behavioral abnormalities, and sudden death under acute and chronic psychological stressors. The impaired S181 phosphorylation of RBM24 inhibits cardiac translation, including APOE translation. Notably, cardiomyocyte-specific expression of APOE rescues cardiac electrophysiological abnormalities and contractile dysfunction, through preventing ROS stress and mitochondrial dysfunction. Moreover, RBM24-S181 phosphorylation acts as a serum marker for chronic stress in human. These results provide a functional link between RBM24 phosphorylation, eIF4E-regulated APOE translation, and psychological-stress-induced CVD.

Date: 2024
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DOI: 10.1038/s41467-024-54519-0

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