Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis,Journal of Advanced Research

当前位置： X-MOL 学术 › J. Adv. Res. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Inhibition of mitophagy via the EIF2S1-ATF4-PRKN pathway contributes to viral encephalitis
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-08-03 , DOI: 10.1016/j.jare.2024.08.003
Xiaowei Song ₁ , Yiliang Wang ₂ , Weixiangmin Zou ₃ , Zexu Wang ₃ , Wenyan Cao ₃ , Minting Liang ₃ , Feng Li ₄ , Qiongzhen Zeng ₃ , Zhe Ren ₃ , Yifei Wang ₃ , Kai Zheng ₅

Affiliation

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.

中文翻译：

通过 EIF2S1-ATF4-PRKN 通路抑制线粒体自噬导致病毒性脑炎

介绍

线粒体自噬是一种负责维持线粒体稳态的选择性自噬形式，可调节抗病毒免疫反应，并作为病毒复制平台促进各种病毒的感染。然而，它在单纯疱疹病毒 1 （HSV-1）感染和单纯疱疹脑炎（HSE）中的确切作用在很大程度上仍然未知。

目标

我们旨在研究 HSV-1 嗜神经性感染对线粒体自噬的调节及其在病毒性脑炎中的作用，并鉴定调节线粒体自噬以影响 HSV-1 感染的小化合物。

方法

通过 Western blot、RT-PCR 和噬菌斑法研究化合物的抗病毒作用。通过 TEM、RT-qPCR、Western blot 和 ELISA 检测 Parkin （PRKN）介导的线粒体自噬和核因子 kappa B （NFKB）介导的神经炎症的变化。通过评估存活率、眼损伤、神经退行性症状、免疫组化分析和组织病理学，在 HSE 小鼠模型中证实了牛磺酸或 PRKN 过表达的治疗效果。

结果

HSV-1 感染导致受损线粒体在 HSE 小鼠的神经元细胞和脑组织中积累。早期 HSV-1 感染导致线粒体自噬激活，随后在后期病毒感染中受到抑制。HSV-1 蛋白 ICP34.5 或 US11 使 EIF2S1-ATF4 轴失调以抑制 PRKN/Parkin mRNA 表达，从而阻碍 PRKN 依赖性线粒体自噬。因此，特异性抑制剂 midiv-1 对线粒体自噬的抑制促进了 HSV-1 感染，而 PRKN 过表达或激动剂（CCCP 和鱼藤酮）的线粒体自噬激活减轻了 HSV-1 感染并减少了 NF-κB 介导的神经炎症。此外，PRKN 过表达小鼠对 HSV-1 感染表现出增强的抵抗力并改善了 HSE 发病机制。此外，牛磺酸是 HSV-1 感染后差异调节的肠道微生物代谢物，作为线粒体自噬激活剂，转录促进 PRKN 表达，刺激线粒体自噬并限制体外和体内的 HSV-1 感染。