UCHL1 deficiency upon HCMV infection induces vascular endothelial inflammatory injury mediated by mitochondrial iron overload

文献类型： 外文期刊

第一作者： Zhu, Wenbo

作者： Zhu, Wenbo;Zhu, Wentong;Wang, Shao;Liu, Shuangquan;Zhang, Hongbo

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关键词： Ubiquitin carboxyl terminal hydrolase-L1; (UCHL1); Ferredoxin reductase (FDXR); Mitochondrial iron overload; AIM2 inflammasome; Pyroptosis

期刊名称：FREE RADICAL BIOLOGY AND MEDICINE （ 影响因子：7.4； 五年影响因子：7.9 ）

ISSN： 0891-5849

年卷期： 2024 年 211 卷

页码：

收录情况： SCI

摘要： Human cytomeglovirus (HCMV) infection predisposes blood vessels to atherosclerosis (AS) and post-transplantation restenosis, but the underlying molecular basis remains elusive. Here, we found that HCMV infection activates AIM2 inflammasome and pyroptosis in vascular endothelial cells by inducing mitochondrial iron overload. Mechanistically, under normal conditions, ubiquitin carboxyl terminal hydrolase-L1 (UCHL1) was identified as a DUB enzyme that interacts with, deubiquitylates, and stabilizes ferredoxin reductase (FDXR), an important mitochondrial protein that regulates mitochondral iron homeostasis. However, HCMV infection in-duces the aberrantly elevated m6A modification and R-loops, the three-stranded DNA-DNA:RNA hybrid struc-tures. The expression of UCHL1 was remarkably reduced by m6A modification-mediated mRNA decay and R-loop-dependent transcriptional termination after HCMV infection. Deficiency of UCHL1 causes ubiquitination and degradation of FDXR. Loss of FDXR induces the mitochondrial iron overload, which consequently leads to AIM2 inflammasome activation and endothelial injury. Moreover, both downregulation expression of UCHL1 and related inflammatory injury in vascular endothelium was observed in MCMV-infected mice. Notably, STM2457, a METTL3 specific inhibitor, restores the expression of UCHL1 upon HCMV infection, thereby inhibiting the inflammatory injury of vascular endothelial cells. Our findings delineate a novel mechnism involved in HCMV-induced inflammatory injury to vascular endothelium and implicate the role of METTL3 inhibitor as a potential therapeutic approach.

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