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Journal of Virology, June 2006, p. 6072-6083, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.02495-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Rongtuan Lin,1,3* Judith Lacoste,1 Peyman Nakhaei,1,2 Qiang Sun,1 Long Yang,1,3 Suzanne Paz,1,2 Peter Wilkinson,1 Ilkka Julkunen,4 Damien Vitour,5 Eliane Meurs,5 and John Hiscott1,2,3*

Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research,1 Departments of Microbiology and Immunology,2 Medicine, McGill University, Montreal, Canada,3 National Public Health Institute and University of Helsinki, Helsinki, Finland,4 Department of Virology, Pasteur Institute, Paris, France5

Received 29 November 2005/ Accepted 4 April 2006

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 IKK{varepsilon} 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 IKK{varepsilon} in the presence of NS3-4A. These observations provide an outline of the mechanism by which hepatitis C virus evades the interferon antiviral response.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, 3755 Cote Ste. Catherine, Montreal H3T 1E2, Quebec, Canada. Phone: (514) 340-8222, ext. 5272. Fax: (514) 340-7576. E-mail for Rongtuan Lin: rongtuan.lin{at}mcgill.ca. E-mail for John Hiscott: john.hiscott{at}mcgill.ca.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, June 2006, p. 6072-6083, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.02495-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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