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

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  • Chiranjeevi Bodda
  • Line S. Reinert
  • Stefanie Fruhwürth, University of Gothenburg
  • ,
  • Timmy Richardo, Hannover Medical School
  • ,
  • Chenglong Sun
  • ,
  • Bao Cun Zhang
  • Maria Kalamvoki, University of Kansas
  • ,
  • Anja Pohlmann, Hannover Medical School
  • ,
  • Trine H. Mogensen
  • Petra Bergström, University of Gothenburg
  • ,
  • Lotta Agholme, University of Gothenburg
  • ,
  • Peter O'Hare, Imperial College London
  • ,
  • Beate Sodeik, Hannover Medical School
  • ,
  • Mads Gyrd-Hansen, University of Oxford
  • ,
  • Henrik Zetterberg, University of Gothenburg, University College London, Sahlgrenska University Hospital
  • ,
  • 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
Article number e20191422
JournalJournal of Experimental Medicine
Publication statusPublished - Jul 2020

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