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Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7.
- Source :
-
PLoS pathogens [PLoS Pathog] 2011 Sep; Vol. 7 (9), pp. e1002247. Date of Electronic Publication: 2011 Sep 08. - Publication Year :
- 2011
-
Abstract
- Recognition of viruses by pattern recognition receptors (PRRs) causes interferon-β (IFN-β) induction, a key event in the anti-viral innate immune response, and also a target of viral immune evasion. Here the vaccinia virus (VACV) protein C6 is identified as an inhibitor of PRR-induced IFN-β expression by a functional screen of select VACV open reading frames expressed individually in mammalian cells. C6 is a member of a family of Bcl-2-like poxvirus proteins, many of which have been shown to inhibit innate immune signalling pathways. PRRs activate both NF-κB and IFN regulatory factors (IRFs) to activate the IFN-β promoter induction. Data presented here show that C6 inhibits IRF3 activation and translocation into the nucleus, but does not inhibit NF-κB activation. C6 inhibits IRF3 and IRF7 activation downstream of the kinases TANK binding kinase 1 (TBK1) and IκB kinase-ε (IKKε), which phosphorylate and activate these IRFs. However, C6 does not inhibit TBK1- and IKKε-independent IRF7 activation or the induction of promoters by constitutively active forms of IRF3 or IRF7, indicating that C6 acts at the level of the TBK1/IKKε complex. Consistent with this notion, C6 immunoprecipitated with the TBK1 complex scaffold proteins TANK, SINTBAD and NAP1. C6 is expressed early during infection and is present in both nucleus and cytoplasm. Mutant viruses in which the C6L gene is deleted, or mutated so that the C6 protein is not expressed, replicated normally in cell culture but were attenuated in two in vivo models of infection compared to wild type and revertant controls. Thus C6 contributes to VACV virulence and might do so via the inhibition of PRR-induced activation of IRF3 and IRF7.
- Subjects :
- Gene Expression Regulation, Viral
Genes, Regulator
HEK293 Cells
Humans
I-kappa B Kinase genetics
I-kappa B Kinase metabolism
Immune Evasion
Immunity, Innate
Interferon Regulatory Factor-3 genetics
Interferon Regulatory Factor-7 genetics
Interferon-beta metabolism
NF-kappa B genetics
NF-kappa B metabolism
Open Reading Frames
Phosphorylation
Plasmids
Protein Binding genetics
Protein Serine-Threonine Kinases genetics
Receptors, Pattern Recognition metabolism
Signal Transduction
Transcription, Genetic
Vaccinia virus metabolism
Vaccinia virus physiology
Viral Proteins metabolism
Virulence Factors genetics
Virulence Factors metabolism
Virus Replication
Interferon Regulatory Factor-3 metabolism
Interferon Regulatory Factor-7 metabolism
Protein Serine-Threonine Kinases metabolism
Vaccinia virus genetics
Viral Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 7
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 21931555
- Full Text :
- https://doi.org/10.1371/journal.ppat.1002247