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

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HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection. / Bodda, Chiranjeevi; Reinert, Line S; Fruhwürth, Stefanie; Richardo, Timmy; Sun, Chenglong; Zhang, Bao-Cun; Kalamvoki, Maria; Pohlmann, Anja; Mogensen, Trine H; Bergström, Petra; Agholme, Lotta; O'Hare, Peter; Sodeik, Beate; Gyrd-Hansen, Mads; Zetterberg, Henrik; Paludan, Søren R.

In: The Journal of Experimental Medicine, Vol. 217, No. 7, 2020.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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 2020, 'HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection', The Journal of Experimental Medicine, vol. 217, no. 7. https://doi.org/10.1084/jem.20191422

APA

Bodda, C., Reinert, L. S., Fruhwürth, S., Richardo, T., Sun, C., Zhang, B-C., Kalamvoki, M., Pohlmann, A., Mogensen, T. H., Bergström, P., Agholme, L., O'Hare, P., Sodeik, B., Gyrd-Hansen, M., Zetterberg, H., & Paludan, S. R. (2020). HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection. The Journal of Experimental Medicine, 217(7). https://doi.org/10.1084/jem.20191422

Vancouver

Bodda C, Reinert LS, Fruhwürth S, Richardo T, Sun C, Zhang B-C et al. HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection. The Journal of Experimental Medicine. 2020;217(7). https://doi.org/10.1084/jem.20191422

Author

Bodda, Chiranjeevi ; Reinert, Line S ; Fruhwürth, Stefanie ; Richardo, Timmy ; Sun, Chenglong ; Zhang, Bao-Cun ; Kalamvoki, Maria ; Pohlmann, Anja ; Mogensen, Trine H ; Bergström, Petra ; Agholme, Lotta ; O'Hare, Peter ; Sodeik, Beate ; Gyrd-Hansen, Mads ; Zetterberg, Henrik ; Paludan, Søren R. / HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection. In: The Journal of Experimental Medicine. 2020 ; Vol. 217, No. 7.

Bibtex

@article{930aebefe62844f8971df37f71ba1c6b,
title = "HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection",
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 = "Animals, Brain/pathology, Cells, Cultured, Cytoplasm/metabolism, DNA, Viral/metabolism, Deubiquitinating Enzymes/metabolism, HEK293 Cells, Herpesvirus 1, Human/metabolism, Humans, Interferon Type I/metabolism, Lysine/metabolism, Membrane Proteins/metabolism, Mice, Inbred C57BL, Microglia/metabolism, Mutation/genetics, Nucleotidyltransferases/metabolism, Protein-Serine-Threonine Kinases/metabolism, Signal Transduction, Ubiquitin/metabolism, Ubiquitination, Viral Proteins/metabolism, Virus Replication/physiology",
author = "Chiranjeevi Bodda and Reinert, {Line S} and Stefanie Fruhw{\"u}rth and Timmy Richardo and Chenglong Sun and Bao-Cun Zhang and Maria Kalamvoki and Anja Pohlmann and Mogensen, {Trine H} and Petra Bergstr{\"o}m and Lotta Agholme and Peter O'Hare and Beate Sodeik and Mads Gyrd-Hansen and Henrik Zetterberg and Paludan, {S{\o}ren R}",
note = "{\textcopyright} 2020 Bodda et al.",
year = "2020",
doi = "10.1084/jem.20191422",
language = "English",
volume = "217",
journal = "The Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "7",

}

RIS

TY - JOUR

T1 - HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection

AU - Bodda, Chiranjeevi

AU - Reinert, Line S

AU - Fruhwürth, Stefanie

AU - Richardo, Timmy

AU - Sun, Chenglong

AU - Zhang, Bao-Cun

AU - Kalamvoki, Maria

AU - Pohlmann, Anja

AU - Mogensen, Trine H

AU - Bergström, Petra

AU - Agholme, Lotta

AU - O'Hare, Peter

AU - Sodeik, Beate

AU - Gyrd-Hansen, Mads

AU - Zetterberg, Henrik

AU - Paludan, Søren R

N1 - © 2020 Bodda et al.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Animals

KW - Brain/pathology

KW - Cells, Cultured

KW - Cytoplasm/metabolism

KW - DNA, Viral/metabolism

KW - Deubiquitinating Enzymes/metabolism

KW - HEK293 Cells

KW - Herpesvirus 1, Human/metabolism

KW - Humans

KW - Interferon Type I/metabolism

KW - Lysine/metabolism

KW - Membrane Proteins/metabolism

KW - Mice, Inbred C57BL

KW - Microglia/metabolism

KW - Mutation/genetics

KW - Nucleotidyltransferases/metabolism

KW - Protein-Serine-Threonine Kinases/metabolism

KW - Signal Transduction

KW - Ubiquitin/metabolism

KW - Ubiquitination

KW - Viral Proteins/metabolism

KW - Virus Replication/physiology

U2 - 10.1084/jem.20191422

DO - 10.1084/jem.20191422

M3 - Journal article

C2 - 32383759

VL - 217

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

SN - 0022-1007

IS - 7

ER -

ID: 280716620