Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity
- Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148
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Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved October 13, 2005 (received for review September 29, 2005)
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-κB 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.
Footnotes
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↵ ‡ To whom correspondence should be addressed. E-mail: zhijian.chen{at}utsouthwestern.edu.
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↵ † X.-D.L., L.S., and R.B.S. contributed equally to this work.
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Author contributions: X.-D.L., L.S., R.B.S., G.P., and Z.C. designed research; X.-D.L., L.S., R.B.S., and G.P. performed research; X.-D.L., L.S., R.B.S., G.P., and Z.C. analyzed data; and Z.C. wrote the paper.
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Conflict of interest statement: No conflicts declared.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: CARD, caspase recruitment domain; HA, hemagglutinin; HCV, hepatitis C virus; IRF3, IFN regulatory factor 3; Luc, luciferase; MAVS, mitochondrial antiviral signaling protein; NS, nonstructural; RIG-I, retinoic acid-induced gene I; SeV, Sendai virus; TM, transmembrane; miniMAVS, truncated MAVS protein containing only the CARD and TM domains.
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See Commentary on page 17539.
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Note. While this manuscript was in preparation, Meylan et al. (12) also reported the identification of MAVS/CARDIF as the target of NS3/4A.
- Copyright © 2005, The National Academy of Sciences
