HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection

Research output: Contribution to journalJournal articleResearchpeer-review

  • Chiranjeevi Bodda
  • Line S Reinert
  • Stefanie Fruhwürth
  • Timmy Richardo
  • Chenglong Sun
  • Bao-Cun Zhang
  • Maria Kalamvoki
  • Anja Pohlmann
  • Trine H Mogensen
  • Petra Bergström
  • Lotta Agholme
  • Peter O'Hare
  • Beate Sodeik
  • Gyrd-Hansen, Mads
  • Henrik Zetterberg
  • Søren R Paludan

Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS-STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. HSV1 ΔDUB also induced elevated IFN expression in murine and human microglia and exhibited reduced viral replication in the brain. This was associated with increased ubiquitination of STING and elevated phosphorylation of STING, TBK1, and IRF3. VP1-2 associated directly with STING, leading to its deubiquitination. Recruitment of VP1-2 to STING was dependent on K150 of STING, which was ubiquitinated by TRIM32. Thus, the DUB activity of HSV1 VP1-2 is a major viral immune-evasion mechanism in the brain.

Original languageEnglish
JournalThe Journal of Experimental Medicine
Issue number7
Publication statusPublished - 2020
Externally publishedYes

Bibliographical note

© 2020 Bodda et al.

    Research areas

  • Animals, Brain/pathology, Cells, Cultured, Cytoplasm/metabolism, DNA, Viral/metabolism, Deubiquitinating Enzymes/metabolism, HEK293 Cells, Herpesvirus 1, Human/metabolism, Humans, Interferon Type I/metabolism, Lysine/metabolism, Membrane Proteins/metabolism, Mice, Inbred C57BL, Microglia/metabolism, Mutation/genetics, Nucleotidyltransferases/metabolism, Protein-Serine-Threonine Kinases/metabolism, Signal Transduction, Ubiquitin/metabolism, Ubiquitination, Viral Proteins/metabolism, Virus Replication/physiology

ID: 280716620