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

Xiao Dong Li, Lijun Sun, Rashu B. Seth, Gabriel Pineda, Zhijian J. Chen

Research output: Contribution to journalArticlepeer-review

578 Scopus citations

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-l 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.

Original languageEnglish (US)
Pages (from-to)17717-17722
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number49
DOIs
StatePublished - Dec 6 2005

Keywords

  • IFN regulatory factor 3
  • Iκb kinase
  • NF-κb
  • Retinoic acid-induced gene i

ASJC Scopus subject areas

  • General

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