Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKε Molecular Complex from the Mitochondrial Outer Membrane by Hepatitis C Virus NS3-4A Proteolytic Cleavage

DOI Web Site 被引用文献8件
  • Rongtuan Lin
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research
  • Judith Lacoste
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research
  • Peyman Nakhaei
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research
  • Qiang Sun
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research
  • Long Yang
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research
  • Suzanne Paz
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research
  • Peter Wilkinson
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research
  • Ilkka Julkunen
    National Public Health Institute and University of Helsinki, Helsinki, Finland
  • Damien Vitour
    Department of Virology, Pasteur Institute, Paris, France
  • Eliane Meurs
    Department of Virology, Pasteur Institute, Paris, France
  • John Hiscott
    Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research

抄録

<jats:title>ABSTRACT</jats:title> <jats:p>Intracellular RNA virus infection is detected by the cytoplasmic RNA helicase RIG-I that plays an essential role in signaling to the host antiviral response. Recently, the adapter molecule that links RIG-I sensing of incoming viral RNA to downstream signaling and gene activation events was characterized by four different groups; MAVS/IPS-1-1/VISA/Cardif contains an amino-terminal CARD domain and a carboxyl-terminal mitochondrial transmembrane sequence that localizes to the mitochondrial membrane. Furthermore, the hepatitis C virus NS3-4A protease complex specifically targets MAVS/IPS-1/VISA/Cardif for cleavage as part of its immune evasion strategy. With a novel search program written in python, we also identified an uncharacterized protein, KIAA1271 (K1271), containing a single CARD-like domain at the N terminus and a Leu-Val-rich C terminus that is identical to that of MAVS/IPS-1/VISA/Cardif. Using a combination of biochemical analysis, subcellular fractionation, and confocal microscopy, we now demonstrate that NS3-4A cleavage of MAVS/IPS-1/VISA/Cardif/K1271 results in its dissociation from the mitochondrial membrane and disrupts signaling to the antiviral immune response. Furthermore, virus-induced IKKε kinase, but not TBK1, colocalized strongly with MAVS at the mitochondrial membrane, and the localization of both molecules was disrupted by NS3-4A expression. Mutation of the critical cysteine 508 to alanine was sufficient to maintain mitochondrial localization of MAVS/IPS-1/VISA/Cardif and IKKε in the presence of NS3-4A. These observations provide an outline of the mechanism by which hepatitis C virus evades the interferon antiviral response.</jats:p>

収録刊行物

  • Journal of Virology

    Journal of Virology 80 (12), 6072-6083, 2006-06-15

    American Society for Microbiology

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