Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection

• Yueh-Ming Loo

  Departments of *Microbiology and

• David M. Owen

  Departments of *Microbiology and

• Kui Li

  Center for Hepatitis Research and

• Andrea K. Erickson

  Departments of *Microbiology and

• Cynthia L. Johnson

  Departments of *Microbiology and

• Penny M. Fish

  Departments of *Microbiology and

• D. Spencer Carney

  Departments of *Microbiology and

• Ting Wang

  Center for Hepatitis Research and

• Hisashi Ishida

  Center for Hepatitis Research and

• Mitsutoshi Yoneyama

  Department of Genetic and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto 606-8501, Japan; and

• Takashi Fujita

  Department of Genetic and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto 606-8501, Japan; and

• Takeshi Saito

  Departments of *Microbiology and

• William M. Lee

  Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;

• Curt H. Hagedorn

  **Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160

• Daryl T.-Y. Lau

  Center for Hepatitis Research and

• Steven A. Weinman

  Center for Hepatitis Research and

• Stanley M. Lemon

  Center for Hepatitis Research and

• Michael Gale

  Departments of *Microbiology and

抄録

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-α/β 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-β 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-β 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.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 103 (15), 6001-6006, 2006-04-11

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1360011146010606592
• NII論文ID: 80019183466
• DOI: 10.1073/pnas.0601523103
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0601523103
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