Zhu Wenbo, Zhang Hongbo, Wang Shao
Clinical Medical Research Center, First Affiliated Hospital, University of South China, Hengyang, China.
Department of Microbiology and Immunology, LSU Health Sciences Center, Shreveport, LA, United States.
Front Microbiol. 2022 Mar 11;13:861734. doi: 10.3389/fmicb.2022.861734. eCollection 2022.
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 mA 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.
人巨细胞病毒（HCMV）感染可诱导血管内皮细胞凋亡，这可能是HCMV所致动脉粥样硬化发生发展的最重要因素。由于尚无清除HCMV感染的特异性药物，因此迫切需要探索能够干预HCMV诱导的动脉粥样硬化的相关药物及机制。本研究证实，维生素D3通过抑制内质网（ER）和线粒体凋亡途径，保护血管内皮细胞免受HCMV诱导的凋亡。机制上，HCMV感染可诱导异常升高的m6A修饰，尤其是甲基转移酶“书写者”（METTL3）和m6A结合蛋白“阅读者”（YTHDF3）的增加。METTL3使线粒体钙单向转运体（MCU）甲基化，MCU是HCMV诱导血管内皮细胞凋亡的主要因素，在3'-UTR的三个m6A位点进行甲基化，促进YTHDF3与甲基化的MCU mRNA结合，随后增加MCU的翻译和表达。进一步分析表明，ALKBH5是MCU mRNA的去甲基化酶“橡皮擦”，可负向调节MCU的m6A修饰过程。相反，维生素D3通过抑制AMPK的激活下调METTL3，从而抑制MCU的m6A修饰和细胞凋亡。我们的研究结果扩展了对m6A驱动机制在病毒诱导的血管内皮损伤中的理解，并突出了维生素D3在干预HCMV诱导的动脉粥样硬化中的意义。
