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 me...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Rockefeller University Press
2020
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| Subjects: |
| _version_ | 1797082262291873792 |
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| author | Bodda, C Reinert, LS Fruhwürth, S Richardo, T Sun, C Zhang, B-C Kalamvoki, M Pohlmann, A Mogensen, TH Bergström, P Agholme, L O'Hare, P Sodeik, B Gyrd-Hansen, M Zetterberg, H Paludan, SR |
| author_facet | Bodda, C Reinert, LS Fruhwürth, S Richardo, T Sun, C Zhang, B-C Kalamvoki, M Pohlmann, A Mogensen, TH Bergström, P Agholme, L O'Hare, P Sodeik, B Gyrd-Hansen, M Zetterberg, H Paludan, SR |
| author_sort | Bodda, C |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T01:25:37Z |
| format | Journal article |
| id | oxford-uuid:91e188f5-253d-4aac-a0f7-f73933e8bd99 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:25:37Z |
| publishDate | 2020 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | oxford-uuid:91e188f5-253d-4aac-a0f7-f73933e8bd992022-03-26T23:21:41ZHSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infectionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:91e188f5-253d-4aac-a0f7-f73933e8bd99Innate immunity and inflammationInfectious disease and host defenseEnglishSymplectic ElementsRockefeller University Press2020Bodda, CReinert, LSFruhwürth, SRichardo, TSun, CZhang, B-CKalamvoki, MPohlmann, AMogensen, THBergström, PAgholme, LO'Hare, PSodeik, BGyrd-Hansen, MZetterberg, HPaludan, SRHerpes 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. |
| spellingShingle | Innate immunity and inflammation Infectious disease and host defense Bodda, C Reinert, LS Fruhwürth, S Richardo, T Sun, C Zhang, B-C Kalamvoki, M Pohlmann, A Mogensen, TH Bergström, P Agholme, L O'Hare, P Sodeik, B Gyrd-Hansen, M Zetterberg, H Paludan, SR HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection |
| title | HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection |
| title_full | HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection |
| title_fullStr | HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection |
| title_full_unstemmed | HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection |
| title_short | HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection |
| title_sort | hsv1 vp1 2 deubiquitinates sting to block type i interferon expression and promote brain infection |
| topic | Innate immunity and inflammation Infectious disease and host defense |
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