HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
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
APA
Vancouver
Author
Bibtex
}
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