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Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms

Academic Article
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Overview

authors

  • Cheng, G.
  • Zhong, J.
  • Chisari, Francis

publication date

  • May 2006

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • The recent establishment of a robust hepatitis C virus (HCV) cell culture system permits analysis of virus-host interactions during HCV infection. Here, we report that HCV genotype 2a (JFH-1) infection fails to induce IFN-beta or IFN-stimulated gene expression in Huh-7 cells, and that it blocks IFN-beta and IFN-stimulated gene production after transfection of synthetic dsRNA. Overexpression of individual components of the dsRNA-signaling pathway in HCV-infected and uninfected cells indicates that HCV inhibits IFN-beta promoter activity by inactivating the mitochondrial antiviral signaling protein/IFN-beta promoter stimulator 1 (MAVS/IPS-1), while leaving the IFN-induced Janus kinases-signal transducers and activators of transcription (JAK-STAT) signaling pathway intact. We also show that MAVS/IPS-1-dependent IFN-beta promoter activity in HCV-infected cells is fully restored by the nonstructural protein 3 (NS3) protease inhibitor BILN2061. In contrast, synthetic dsRNA-induced IFN-beta promoter activity is not restored by BILN2061, although it is partially restored by overexpression of RIG-I. These results support recently reported evidence that the HCV NS3 protease blunts the ability of HCV to induce IFN-beta promoter activity by proteolytically cleaving MAVS/IPS-1. The results also suggest that HCV blocks the synthetic dsRNA-induced signaling pathway at a point upstream of MAVS/IPS-1, and that it does so by an NS3-independent mechanism.

subject areas

  • Active Transport, Cell Nucleus
  • Carbamates
  • Cell Line, Tumor
  • Gene Expression Regulation, Viral
  • Hepacivirus
  • Humans
  • I-kappa B Kinase
  • Interferon Regulatory Factor-3
  • Interferon-Stimulated Gene Factor 3
  • Interferon-beta
  • Macrocyclic Compounds
  • Promoter Regions, Genetic
  • Protease Inhibitors
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Quinolines
  • RNA, Double-Stranded
  • Response Elements
  • Signal Transduction
  • Thiazoles
  • Viral Nonstructural Proteins
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Research

keywords

  • IFN-stimulated genes
  • nonstructural protein 3/4A
  • retinoic acid-induced gene I
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Identity

PubMed Central ID

  • PMC1482521

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0602957103

PubMed ID

  • 16707574
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Additional Document Info

start page

  • 8499

end page

  • 8504

volume

  • 103

issue

  • 22

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