HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
Open Access
- 8 May 2020
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 217 (7)
- https://doi.org/10.1084/jem.20191422
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.Keywords
Funding Information
- European Research Council (786602)
- Novo Nordisk Foundation (NNF18OC0030274)
- Lundbeck Foundation (R198-2015-171, R268-2016-3927)
- EU FP7 Mobilex (4092-00253)
- Ludwig Institute for Cancer Research
- Wellcome Trust (102894/Z/13/Z)
- Deutsche Forschungsgemeinschaft (39087428)
- Swedish Research Council (2018-02532)
- European Research Council (681712)
- Swedish State Support for Clinical Research (ALFGBG-720931)
- UK Dementia Research Institute
- Alzheimer’s Drug Discovery Foundation
This publication has 64 references indexed in Scilit:
- Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 proteinProceedings of the National Academy of Sciences of the United States of America, 2012
- Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhoodThe Journal of Experimental Medicine, 2012
- Inhibition of RIG-I-Mediated Signaling by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Deubiquitinase ORF64Journal of Virology, 2011
- Autocatalytic Activity of the Ubiquitin-Specific Protease Domain of Herpes Simplex Virus 1 VP1-2Journal of Virology, 2011
- Recognition of herpesviruses by the innate immune systemNature Reviews Immunology, 2011
- Human TRAF3 Adaptor Molecule Deficiency Leads to Impaired Toll-like Receptor 3 Response and Susceptibility to Herpes Simplex EncephalitisImmunity, 2010
- Pattern Recognition Receptors and InflammationCell, 2010
- STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunityNature, 2009
- Control of TANK-binding Kinase 1-mediated Signaling by the γ134.5 Protein of Herpes Simplex Virus 1Online Journal of Public Health Informatics, 2009
- Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signalingVirology, 2008