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Journal of Advanced Research

Journal of Advanced Research

IF: 11.4
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Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis.

Published:3 August 2024 DOI: 10.1016/j.jare.2024.08.003 PMID: 39103048
Xiaowei Song , Yiliang Wang , Weixiangmin Zou , Zexu Wang , Wenyan Cao , Minting Liang , Feng Li , Qiongzhen Zeng , Zhe Ren , Yifei Wang , Kai Zheng

Abstract

Introduction

Mitophagy, a selective form of autophagy responsible for maintaining mitochondrial homeostasis, regulates the antiviral immune response and acts as viral replication platforms to facilitate infection with various viruses. However, its precise role in herpes simplex virus 1 (HSV-1) infection and herpes simplex encephalitis (HSE) remains largely unknown.

Objectives

We aimed to investigate the regulation of mitophagy by HSV-1 neurotropic infection and its role in viral encephalitis, and to identify small compounds that regulate mitophagy to affect HSV-1 infection.

Methods

The antiviral effects of compounds were investigated by Western blot, RT-PCR and plaque assay. The changes of Parkin (PRKN)-mediated mitophagy and Nuclear Factor kappa B (NFKB)-mediated neuroinflammation were examined by TEM, RT-qPCR, Western blot and ELISA. The therapeutic effect of taurine or PRKN-overexpression was confirmed in the HSE mouse model by evaluating survival rate, eye damage, neurodegenerative symptoms, immunohistochemistry analysis and histopathology.

Results

HSV-1 infection caused the accumulation of damaged mitochondria in neuronal cells and in the brain tissue of HSE mice. Early HSV-1 infection led to mitophagy activation, followed by inhibition in the later viral infection. The HSV-1 proteins ICP34.5 or US11 deregulated the EIF2S1-ATF4 axis to suppress PRKN/Parkin mRNA expression, thereby impeding PRKN-dependent mitophagy. Consequently, inhibition of mitophagy by specific inhibitor midiv-1 promoted HSV-1 infection, whereas mitophagy activation by PRKN overexpression or agonists (CCCP and rotenone) attenuated HSV-1 infection and reduced the NF-κB-mediated neuroinflammation. Moreover, PRKN-overexpressing mice showed enhanced resistance to HSV-1 infection and ameliorated HSE pathogenesis. Furthermore, taurine, a differentially regulated gut microbial metabolite upon HSV-1 infection, acted as a mitophagy activator that transcriptionally promotes PRKN expression to stimulate mitophagy and to limit HSV-1 infection both in vitro and in vivo.

Conclusion

These results reveal the protective function of mitophagy in HSE pathogenesis and highlight mitophagy activation as a potential antiviral therapeutic strategy for HSV-1-related diseases.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
TRAUMATIC ACID 6402-36-4 C12H20O4 118 suppliers $28.00-$1469.00
TRAUMATIC ACID 6402-36-4 C12H20O4 118 suppliers $28.00-$1469.00
TRAUMATIC ACID 6402-36-4 C12H20O4 118 suppliers $28.00-$1469.00
TRAUMATIC ACID 6402-36-4 C12H20O4 118 suppliers $28.00-$1469.00

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