Viral suppression of innate immunity via spatial isolation of TBK1/IKKε from mitochondrial antiviral platform

J Mol Cell Biol. 2014 Aug;6(4):324-37. doi: 10.1093/jmcb/mju015. Epub 2014 Apr 4.

Abstract

For antiviral signaling mediated by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), the recruitment of cytosolic RLRs and downstream molecules (such as TBK1 and IKKε) to mitochondrial platform is a central event that facilitates the establishment of host antiviral state. Here, we present an example of viral targeting for immune evasion through spatial isolation of TBK1/IKKε from mitochondrial antiviral platform, which was employed by severe fever with thrombocytopenia syndrome virus (SFTSV), a deadly bunyavirus emerging recently. We showed that SFTSV nonstructural protein NSs functions as the interferon (IFN) antagonist, mainly via suppressing TBK1/IKKε-IRF3 signaling. NSs mediates the formation of cytoplasmic inclusion bodies (IBs), and the blockage of IB formation impairs IFN-inhibiting activity of NSs. We next demonstrate that IBs are utilized to compartmentalize TBK1/IKKε. The compartmentalization results in spatial isolation of the kinases from mitochondria, and deprived TBK1/IKKε may participate in antiviral complex assembly, leading to the blockage of IFN induction. This study proposes a new role of viral IBs as virus-built 'jail' for imprisoning cellular factors and presents a novel and likely common mechanism of viral immune evasion through spatial isolation of critical signaling molecules from the mitochondrial antiviral platform.

Keywords: TBK1/IKKε; immune evasion; inclusion bodies; innate immunity; severe fever with thrombocytopenia syndrome virus; spatial isolation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Blotting, Western
  • Fluorescent Antibody Technique
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Immunity, Innate / immunology*
  • Immunoprecipitation
  • Inclusion Bodies, Viral / immunology
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Mitochondria / immunology*
  • Mitochondria / metabolism
  • Mitochondria / virology
  • Phlebotomus Fever / immunology
  • Phlebotomus Fever / metabolism*
  • Phlebotomus Fever / virology
  • Phlebovirus / genetics
  • Phlebovirus / immunology*
  • Phlebovirus / metabolism
  • Promoter Regions, Genetic
  • Protein Interaction Maps
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Response Elements / genetics
  • Signal Transduction
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / immunology*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Viral Nonstructural Proteins
  • Interferon-beta
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase