期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 49, 页码 17717-17722出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0508531102
关键词
IFN regulatory factor 3; NF-kappa B; retinoic acid-induced gene; I kappa B kinase
资金
- NCRR NIH HHS [S10 RR019406, 1-S10-RR19406] Funding Source: Medline
- NIAID NIH HHS [R01-AI60919] Funding Source: Medline
- NIGMS NIH HHS [F31 GM068979] Funding Source: Medline
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-kappa B and IFN regulatory factor 3 to induce type-1 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.
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