1. Academic Validation
  2. WHSC1L1-mediated epigenetic downregulation of VMP1 participates in herpes simplex virus 1 infection-induced mitophagy impairment and neuroinflammation

WHSC1L1-mediated epigenetic downregulation of VMP1 participates in herpes simplex virus 1 infection-induced mitophagy impairment and neuroinflammation

  • Mol Immunol. 2023 Sep 23;163:63-74. doi: 10.1016/j.molimm.2023.09.012.
Yan Yao 1 Juxian Gu 2 Meng Li 2 Guoce Li 3 Jingyi Ai 2 Li Zhao 2
Affiliations

Affiliations

  • 1 Department of Neurology, Cangzhou Central Hospital, Cangzhou 061001, Hebei, PR China. Electronic address: yaoyan7221@163.com.
  • 2 Department of Neurology, Cangzhou Central Hospital, Cangzhou 061001, Hebei, PR China.
  • 3 Department of MRI, Cangzhou Central Hospital, Cangzhou 061001, Hebei, PR China.
Abstract

Microglia are the first-line defenders against invading pathogens in the brain whose activation mediates virus clearance and leads to neurotoxicity as well. This work studies the role of Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1)/vacuole membrane protein 1 (VMP1) interaction in the activation of microglia and neuroinflammation following herpes simplex virus 1 (HSV-1) Infection. Aberrantly expressed genes after HSV-1 Infection were screened by analyzing the GSE35943 dataset. C57BL/6J mice and mouse microglia BV2 were infected with HSV-1 for in vivo and in vitro assays. VMP1 was downregulated but WHSC1L1 was upregulated in HSV-1-infected mouse brain tissues as well as in BV2 cells. The VMP1 overexpression enhanced Mitophagy activity and suppressed oxidative stress and inflammatory activation of BV2 cells, but these effects were blocked by the Autophagy antagonist 3-methyladenine. WHSC1H1 suppressed VMP1 transcription through H3K36me2-recruited DNMT3A. Downregulation of WHSC1H1 similarly enhanced Mitophagy in BV2 cells, and it alleviated microglia activation, nerve cell inflammation, and brain tissue damage in HSV-1-infected mice. However, the alleviating roles of WHSC1H1 silencing were negated by further VMP1 silencing. Taken together. this study demonstrates that WHSC1L1 upregulation following HSV-1 Infection leads to Mitophagy impairment and neuroinflammation through epigenetic suppression of VMP1.

Keywords

Herpes simplex encephalitis; Microglia; Mitophagy; VMP1; WHSC1L1.

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