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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
15
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pubmed:dateCreated |
2006-4-12
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pubmed:abstractText |
Viral signaling through retinoic acid-inducible gene-I (RIG-I) and its adaptor protein, IFN promoter-stimulator 1 (IPS-1), activates IFN regulatory factor-3 (IRF-3) and the host IFN-alpha/beta response that limits virus infection. The hepatitis C virus (HCV) NS3/4A protease cleaves IPS-1 to block RIG-I signaling, but how this regulation controls the host response to HCV is not known. Moreover, endogenous IPS-1 cleavage has not been demonstrated in the context of HCV infection in vitro or in vivo. Here, we show that HCV infection transiently induces RIG-I- and IPS-1-dependent IRF-3 activation. This host response limits HCV production and constrains cellular permissiveness to infection. However, HCV disrupts this response early in infection by NS3/4A cleavage of IPS-1 at C508, releasing IPS-1 from the mitochondrial membrane. Cleavage results in subcellular redistribution of IPS-1 and loss of interaction with RIG-I, thereby preventing downstream activation of IRF-3 and IFN-beta induction. Liver tissues from chronically infected patients similarly demonstrate subcellular redistribution of IPS-1 in infected hepatocytes and IPS-1 cleavage associated with a lack of ISG15 expression and conjugation of target proteins in vivo. Importantly, small-molecule inhibitors of NS3/4A prevent cleavage and restore RIG-I signaling of IFN-beta induction. Our results suggest a dynamic model in which early activation of IRF-3 and induction of antiviral genes are reversed by IPS-1 proteolysis and abrogation of RIG-I signaling as NS3/4A accumulates in newly infected cells. HCV protease inhibitors effectively prevent IPS-1 proteolysis, suggesting they may be capable of restoring this innate host response in clinical practice.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-11070172,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-11424123,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-11544356,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-11861865,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-11991981,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-12702807,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-12761501,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-14578911,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-14647057,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-14724833,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-15208624,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-15273323,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-15351350,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-15708988,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-15710891,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-15710892,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-15939869,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-15998442,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16039576,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16087332,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16107832,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16116171,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16122679,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16125763,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16127453,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16153868,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16177806,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16199211,
http://linkedlifedata.com/resource/pubmed/commentcorrection/16585524-16227280
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0027-8424
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pubmed:author |
pubmed-author:CarneyD SpencerDS,
pubmed-author:EricksonAndrea KAK,
pubmed-author:FishPenny MPM,
pubmed-author:FujitaTakashiT,
pubmed-author:GaleMichaelMJr,
pubmed-author:HagedornCurt HCH,
pubmed-author:IshidaHisashiH,
pubmed-author:JohnsonCynthia LCL,
pubmed-author:KAYAA,
pubmed-author:LauDaryl T-YDT,
pubmed-author:LeeWilliam MWM,
pubmed-author:LemonStanley MSM,
pubmed-author:LooYueh-MingYM,
pubmed-author:OwenDavid MDM,
pubmed-author:SaitoTakeshiT,
pubmed-author:WangTingT,
pubmed-author:WeinmanSteven ASA,
pubmed-author:YoneyamaMitsutoshiM
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pubmed:issnType |
Print
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pubmed:day |
11
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pubmed:volume |
103
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6001-6
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:16585524-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:16585524-Carcinoma, Hepatocellular,
pubmed-meshheading:16585524-Cell Line, Tumor,
pubmed-meshheading:16585524-Genetic Variation,
pubmed-meshheading:16585524-Hepacivirus,
pubmed-meshheading:16585524-Hepatitis C,
pubmed-meshheading:16585524-Humans,
pubmed-meshheading:16585524-Interferon Regulatory Factor-3,
pubmed-meshheading:16585524-Liver Neoplasms,
pubmed-meshheading:16585524-Mitochondria
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pubmed:year |
2006
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pubmed:articleTitle |
Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection.
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pubmed:affiliation |
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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