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UCHL1 deficiency upon HCMV infection induces vascular endothelial inflammatory injury mediated by mitochondrial iron
Wenbo Zhu1, Wentong Zhu2, Shao Wang3
1The First Affiliated Hospital, Clinical Medical Research Center, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
Abstract:
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 induces the aberrantly elevated m6A modification and R-loops, the three-stranded DNA-DNA:RNA hybrid structures. 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.
Insights
Human cytomegalovirus (HCMV) infection causes vascular endothelial injury by inducing mitochondrial iron overload. METTL3 inhibitors may offer a therapeutic strategy against HCMV-driven atherosclerosis and restenosis.
Area of Science:
- Vascular Biology
- Infectious Diseases
- Molecular Mechanisms
Background:
- Human cytomegalovirus (HCMV) infection is linked to atherosclerosis and restenosis.
- The molecular mechanisms underlying HCMV-induced vascular damage are not fully understood.
Purpose of the Study:
- To elucidate the molecular pathways linking HCMV infection to vascular endothelial injury.
- To identify potential therapeutic targets for HCMV-associated vascular diseases.
Main Methods:
- Investigated HCMV-induced changes in vascular endothelial cells.
- Utilized biochemical assays, molecular biology techniques, and mouse models.
- Examined the role of UCHL1, FDXR, mitochondrial iron, and AIM2 inflammasome activation.
- Tested the efficacy of a METTL3 inhibitor (STM2457).
Main Results:
- HCMV infection activates AIM2 inflammasome and pyroptosis via mitochondrial iron overload.
- HCMV reduces UCHL1 expression through m6A modification and R-loops, leading to FDXR degradation.
- Loss of FDXR causes mitochondrial iron overload and endothelial injury.
- UCHL1 downregulation and endothelial inflammation were observed in MCMV-infected mice.
- STM2457 restored UCHL1 expression and inhibited HCMV-induced endothelial inflammation.
Conclusions:
- HCMV infection triggers vascular endothelial injury through a novel pathway involving UCHL1, FDXR, and mitochondrial iron overload.
- METTL3 inhibition presents a promising therapeutic avenue for managing HCMV-related vascular complications.
