Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7

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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. / Unterholzner, Leonie; Sumner, Rebecca P.; Baran, Marcin et al.
In: PLoS Pathogens, Vol. 7, No. 9, e1002247, 09.2011.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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@article{90b2cad3d4bb4645841a99ab635a9e9b,

title = "Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7",

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.",

keywords = "Gene Expression Regulation, Viral, Genes, Regulator, HEK293 Cells, Humans, I-kappa B Kinase, Immune Evasion, Immunity, Innate, Interferon Regulatory Factor-3, Interferon Regulatory Factor-7, Interferon-beta, NF-kappa B, Open Reading Frames, Phosphorylation, Plasmids, Protein Binding, Protein-Serine-Threonine Kinases, Receptors, Pattern Recognition, Signal Transduction, Transcription, Genetic, Vaccinia virus, Viral Proteins, Virulence Factors, Virus Replication",

author = "Leonie Unterholzner and Sumner, {Rebecca P.} and Marcin Baran and Hongwei Ren and Mansur, {Daniel S.} and Bourke, {Nollaig M.} and Felix Randow and Smith, {Geoffrey L.} and Bowie, {Andrew G.}",

year = "2011",

month = sep,

doi = "10.1371/journal.ppat.1002247",

language = "English",

volume = "7",

journal = "PLoS Pathogens",

issn = "1553-7366",

publisher = "Public Library of Science",

number = "9",

}

RIS

TY - JOUR

T1 - Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7

AU - Unterholzner, Leonie

AU - Sumner, Rebecca P.

AU - Baran, Marcin

AU - Ren, Hongwei

AU - Mansur, Daniel S.

AU - Bourke, Nollaig M.

AU - Randow, Felix

AU - Smith, Geoffrey L.

AU - Bowie, Andrew G.

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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.

KW - Gene Expression Regulation, Viral

KW - Genes, Regulator

KW - HEK293 Cells

KW - Humans

KW - I-kappa B Kinase

KW - Immune Evasion

KW - Immunity, Innate

KW - Interferon Regulatory Factor-3

KW - Interferon Regulatory Factor-7

KW - Interferon-beta

KW - NF-kappa B

KW - Open Reading Frames

KW - Phosphorylation

KW - Plasmids

KW - Protein Binding

KW - Protein-Serine-Threonine Kinases

KW - Receptors, Pattern Recognition

KW - Signal Transduction

KW - Transcription, Genetic

KW - Vaccinia virus

KW - Viral Proteins

KW - Virulence Factors

KW - Virus Replication

U2 - 10.1371/journal.ppat.1002247

DO - 10.1371/journal.ppat.1002247

M3 - Journal article

C2 - 21931555

VL - 7

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 9

M1 - e1002247

ER -

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