Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKepsilon molecular complex from the mitochondrial outer membrane by hepatitis C virus NS3-4A proteolytic cleavage.

Abstract

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

• Authors: Rongtuan Lin, Judith Lacoste, Peyman Nakhaei, Qiang Sun, Long Yang, Suzanne Paz, Peter Wilkinson, Ilkka Julkunen, Damien Vitour, Eliane Meurs, John Hiscott
• Journal: Journal of virology (J Virol) Vol. 80 Issue 12 Pg. 6072-83 (Jun 2006) ISSN: 0022-538X [Print] United States
• PMID: 16731946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• MAVS protein, human
• Mitochondrial Proteins
• Multiprotein Complexes
• NS3 protein, hepatitis C virus
• Viral Nonstructural Proteins
• I-kappa B Kinase
• Peptide Hydrolases

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Hepacivirus (chemistry)
• Humans
• I-kappa B Kinase (metabolism)
• Intracellular Membranes (metabolism)
• Mitochondria (ultrastructure)
• Mitochondrial Proteins (metabolism)
• Multiprotein Complexes (metabolism)
• Peptide Hydrolases (metabolism)
• Signal Transduction (immunology)
• Viral Nonstructural Proteins (metabolism)