HSV1 VP1-2 Deubiquitinates STING to Block Type I Interferon Expression and Promote Brain Infection

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2020 May 9

PMID 32383759

Citations 50

Authors

Chiranjeevi Bodda

Line S Reinert

Stefanie Fruhwurth

Timmy Richardo

Chenglong Sun

Bao-Cun Zhang

Maria Kalamvoki

Anja Pohlmann

Trine H Mogensen

Petra Bergstrom

Lotta Agholme

Peter OHare

Beate Sodeik

Mads Gyrd-Hansen

Henrik Zetterberg

Soren R Paludan

Affiliations

Soon will be listed here.

Abstract

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.

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