Dysregulated RBM24 phosphorylation impairs APOE translation underlying psychological stress-induced cardiovascular disease
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.
Authors
- Shaoxiang Luo
- Landong Li (ORCID: https://orcid.org/0000-0003-0998-4061)
- Yufeng Yao (ORCID: https://orcid.org/0000-0003-0395-3993)
- Min Zhang (ORCID: https://orcid.org/0000-0003-4927-2624)
- Yang He (ORCID: https://orcid.org/0000-0001-9171-5500)
- Yusheng Bian (ORCID: https://orcid.org/0000-0003-1163-5231)
- Lei Sun (ORCID: https://orcid.org/0000-0002-0757-8476)
- Guanhua Su (ORCID: https://orcid.org/0000-0001-8793-8146)
- Zhiqiang Dong (ORCID: https://orcid.org/0000-0001-6259-915X)
- Xuemei Bai (ORCID: https://orcid.org/0000-0002-9711-4199)
- Bingcheng Cai
- Dong-Jun Lv (ORCID: https://orcid.org/0000-0001-7443-2445)
- Xiaoyu Zhang (ORCID: https://orcid.org/0000-0001-6243-817X)
- Qing Kenneth Wang (ORCID: https://orcid.org/0000-0002-2235-6572)
- Bo Li (ORCID: https://orcid.org/0000-0002-2812-1328)
- Chi Zhang (ORCID: https://orcid.org/0000-0002-4238-6015)
- Hui Li (ORCID: https://orcid.org/0000-0001-5578-7259)
- Fang Chen (ORCID: https://orcid.org/0000-0003-0189-618X)
- Zhuowei Huang
- Zepeng Tu
- Xudong Han (ORCID: https://orcid.org/0000-0002-2160-9830)
- Bingbing Du
Institutions
- Union Hospital (HK)
- Shandong University (CN)
- Huazhong Agricultural University (CN)
- Jinhua University of Vocational Technology (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-23
- DOI
- https://doi.org/10.1038/s41467-024-54519-0
- Citations
- 9
- Primary Topic
- Cardiovascular Function and Risk Factors
- Type
- article
- Field-Weighted Citation Impact
- 3.62
Funders
- Shandong University