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Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17717-22. Epub 2005 Nov 21.

Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity.

Author information

1
Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.

Abstract

Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the mitochondrial antiviral signaling protein, MAVS, that activates NF-kappaB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host-pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.

PMID:
16301520
PMCID:
PMC1308909
DOI:
10.1073/pnas.0508531102
[Indexed for MEDLINE]
Free PMC Article

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