HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
Copyright policy )HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
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.
- University of Kansas United States
- Aarhus University Denmark
- Ludwig Cancer Research United Kingdom
- University of Oxford United Kingdom
- Hannover Medical School Germany
570, Cytoplasm, Infectious disease and host defense, Immunology, 610, Innate immunity and inflammation, Herpesvirus 1, Human, Protein Serine-Threonine Kinases, Article, Animals, Humans, 11 Medical and Health Sciences, Cells, Cultured, Deubiquitinating Enzymes, Ubiquitin, Lysine, Ubiquitination, Brain, Membrane Proteins, Nucleotidyltransferases, Mice, Inbred C57BL, HEK293 Cells, DNA, Viral, Interferon Type I, Mutation, Microglia, Signal Transduction
570, Cytoplasm, Infectious disease and host defense, Immunology, 610, Innate immunity and inflammation, Herpesvirus 1, Human, Protein Serine-Threonine Kinases, Article, Animals, Humans, 11 Medical and Health Sciences, Cells, Cultured, Deubiquitinating Enzymes, Ubiquitin, Lysine, Ubiquitination, Brain, Membrane Proteins, Nucleotidyltransferases, Mice, Inbred C57BL, HEK293 Cells, DNA, Viral, Interferon Type I, Mutation, Microglia, Signal Transduction
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