Functional and therapeutic analysis of hepatitis C virus NS3·4A protease control of antiviral immune defense

Cynthia L. Johnson, David M. Owen, Michael Gale

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Chronic hepatitis C virus (HCV) infection is a major global public health problem. HCV infection is supported by viral strategies to evade the innate antiviral response wherein the viral NS3·4A protease complex targets and cleaves the interferon promoter stimulator-1 (IPS-1) adaptor protein to ablate signaling of interferon α/β immune defenses. Here we examined the structural requirements of NS3·4A and the therapeutic potential of NS3·4A inhibitors to control the innate immune response against virus infection. The structural composition of NS3 includes an amino-terminal serine protease domain and a carboxyl-terminal RNA helicase domain. NS3 mutants lacking the helicase domain retained the ability to control virus signaling initiated by retinoic acid-inducible gene-I (RIG-I) or melanoma differentiation antigen 5 and suppressed the downstream activation of interferon regulatory factor-3 (IRF-3) and nuclear factor κB (NF-κB) through the targeted proteolysis of IPS-1. This regulation was abrogated by truncation of the NS3 protease domain or by point mutations that ablated protease activity. NS3·4A protease control of antiviral immune signaling was due to targeted proteolysis of IPS-1 by the NS3 protease domain and minimal NS4A cofactor. Treatment of HCV-infected cells with an NS3 protease inhibitor prevented IPS-1 proteolysis by the HCV protease and restored RIG-I immune defense signaling during infection. Thus, the NS3·4A protease domain can target IPS-1 for cleavage and is essential for blocking RIG-I signaling to IRF-3 and NF-κB, whereas the helicase domain is dispensable for this action. Our results indicate that NS3·4A protease inhibitors have immunomodulatory potential to restore innate immune defenses to HCV infection.

Original languageEnglish (US)
Pages (from-to)10792-10803
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number14
DOIs
StatePublished - Apr 6 2007

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Viruses
Hepacivirus
Antiviral Agents
Peptide Hydrolases
Interferons
Virus Diseases
Proteolysis
Tretinoin
Interferon Regulatory Factor-3
Genes
Protease Inhibitors
Therapeutics
RNA Helicases
Melanoma-Specific Antigens
Differentiation Antigens
Serine Proteases
Public health
Chronic Hepatitis C
Medical problems
Point Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Functional and therapeutic analysis of hepatitis C virus NS3·4A protease control of antiviral immune defense. / Johnson, Cynthia L.; Owen, David M.; Gale, Michael.

In: Journal of Biological Chemistry, Vol. 282, No. 14, 06.04.2007, p. 10792-10803.

Research output: Contribution to journalArticle

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