Encephalomyocarditis virus 3C protease attenuates type I interferon production through disrupting the TANK-TBK1-IKKε-IRF3 complex

Biochem J. 2017 Jun 9;474(12):2051-2065. doi: 10.1042/BCJ20161037.

Abstract

TRAF family member-associated NF-κB activator (TANK) is a scaffold protein that assembles into the interferon (IFN) regulator factor 3 (IRF3)-phosphorylating TANK-binding kinase 1 (TBK1)-(IκB) kinase ε (IKKε) complex, where it is involved in regulating phosphorylation of the IRF3 and IFN production. However, the functions of TANK in encephalomyocarditis virus (EMCV) infection-induced type I IFN production are not fully understood. Here, we demonstrated that, instead of stimulating type I IFN production, the EMCV-HB10 strain infection potently inhibited Sendai virus- and polyI:C-induced IRF3 phosphorylation and type I IFN production in HEK293T cells. Mechanistically, EMCV 3C protease (EMCV 3C) cleaved TANK and disrupted the TANK-TBK1-IKKε-IRF3 complex, which resulted in the reduction in IRF3 phosphorylation and type I IFN production. Taken together, our findings demonstrate that EMCV adopts a novel strategy to evade host innate immune responses through cleavage of TANK.

Keywords: 3C protease; IKKε; TANK; TBK1; encephalomyocarditis virus; interferon.

MeSH terms

  • 3C Viral Proteases
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Substitution
  • Animals
  • Cell Line
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Dogs
  • Encephalomyocarditis virus / enzymology*
  • Gene Deletion
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / chemistry
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Interferon Regulatory Factor-3 / antagonists & inhibitors*
  • Interferon Regulatory Factor-3 / chemistry
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / antagonists & inhibitors*
  • Interferon Type I / biosynthesis
  • Mesocricetus
  • Mutagenesis, Site-Directed
  • Mutation
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Phosphorylation
  • Protein Multimerization
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proteolysis
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Viral Proteins / chemistry
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • TANK protein, human
  • Viral Proteins
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • IKBKE protein, human
  • Cysteine Endopeptidases
  • 3C Viral Proteases