Vitamin D3 Suppresses Human Cytomegalovirus-Induced Vascular Endothelial Apoptosis via Rectification of Paradoxical m6A Modification of Mitochondrial Calcium Uniporter mRNA, Which Is Regulated by METTL3 and YTHDF3
文献类型： 外文期刊
作者： Zhu, Wenbo 1 ; Zhang, Hongbo 1 ; Wang, Shao 3 ;
作者机构： 1.Univ South China, Affiliated Hosp 1, Clin Med Res Ctr, Hengyang, Peoples R China
2.LSU Hlth Sci Ctr, Dept Microbiol & Immunol, Shreveport, LA 71103 USA
3.Fujian Acad Agr Sci, Inst Anim Husb & Vet Med, Fuzhou, Peoples R China
关键词： HCMV; vascular endothelial cells; apoptosis; MCU; m6A modification
期刊名称：FRONTIERS IN MICROBIOLOGY （ 影响因子：6.064； 五年影响因子：6.843 ）
ISSN：
年卷期： 2022 年 13 卷
页码：
收录情况： SCI
摘要： Human cytomegalovirus (HCMV) infection can induce apoptosis of vascular endothelial cells, which may be the most important element of development and progression of reported atherosclerosis caused by HCMV. As there are no specific drugs to clear HCMV infection, exploration of relevant drugs and mechanisms that can intervene in HCMV-induced atherosclerosis is urgently needed. The present study confirmed that vitamin D3 protected vascular endothelial cells from HCMV-induced apoptosis by inhibiting endoplasmic reticulum (ER) and mitochondrial apoptosis pathway. Mechanistically, HCMV infection could induce aberrantly elevated m6A modification, especially the increases of methyltransferases-"writers" (METTL3) and m(6)A binding proteins-"readers" (YTHDF3). METTL3 methylates mitochondrial calcium uniporter (MCU), the main contributor to HCMV-induced apoptosis of vascular endothelial cells, at three m6A residues in the 3 '-UTR, which promotes the association of the YTHDF3 with methylated MCU mRNA and subsequently increases the translation and expression of MCU. Further analysis shows that ALKBH5 is the demethylases-"eraser" of MCU mRNA, which can negatively regulate the m6A modification process of MCU. Conversely, vitamin D3 downregulated the METTL3 by inhibiting the activation of AMPK, thereby inhibiting the m6A modification of MCU and cell apoptosis. Our findings extend the understanding of m6A driven machinery in virus-induced vascular endothelium damage and highlight the significance of vitamin D3 in the intervention of HCMV-induced atherosclerosis.
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