Hepatitis C virus NS2 protease inhibits host cell antiviral response by inhibiting IKK[epsi] and TBK1 functions

Hepatitis C virus (HCV) encodes for several proteins that can interfere with host cell signaling and antiviral response. Previously, serine protease NS3/4A was shown to block host cell interferon (IFN) production by proteolytic cleavage of MAVS and TRIF, the adaptor molecules of the RIG-I and TLR3 s...

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Bibliographic Details
Published in:Journal of medical virology 2013-01, Vol.85 (1), p.71
Main Authors: Kaukinen, Pasi, Sillanpaa, Maarit, Nousiainen, Laura, Melen, Krister, Julkunen, Ilkka
Format: Article
Language:English
Subjects:
Hepatitis
Kinases
Pharmacology
Protease inhibitors
Virology
Online Access:Get full text
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Summary:Hepatitis C virus (HCV) encodes for several proteins that can interfere with host cell signaling and antiviral response. Previously, serine protease NS3/4A was shown to block host cell interferon (IFN) production by proteolytic cleavage of MAVS and TRIF, the adaptor molecules of the RIG-I and TLR3 signaling pathways, respectively. This study shows that another HCV protease, NS2 can interfere efficiently with cytokine gene expression. NS2 and its proteolytically inactive mutant forms were able to inhibit type I and type III IFN, CCL5 and CXCL10 gene promoters activated by Sendai virus infection. However, the CXCL8 gene promoter was not inhibited by NS2. In addition, constitutively active RIG-I ([Delta]RIG-I), MAVS, TRIF, IKK[epsi], and TBK1-induced activation of IFN-[beta] promoter was inhibited by NS2. Cotransfection experiments with IKK[epsi] or TBK1 together with interferon regulatory factor 3 (IRF3) and HCV expression constructs revealed that NS2 in a dose-dependent manner inhibited IKK[epsi] and especially TBK1-induced IRF3 phosphorylation. GST pull-down experiments with GST-NS2 and in vitro-translated and cell-expressed IKK[epsi] and TBK1 demonstrated direct physical interactions of the kinases with NS2. Further evidence that the IKK[epsi]/TBK1 kinase complex is the target for NS2 was obtained from the observation that the constitutively active form of IRF3 (IRF3-5D) activated readily IFN-[beta] promoter in the presence of NS2. The present study identified HCV NS2 as a potent interferon antagonist, and describes an explanation of how NS2 downregulates the major signaling pathways involved in the development of host innate antiviral responses. J. Med. Virol. 85:71-82, 2012. © 2012 Wiley Periodicals, Inc. [PUBLICATION ABSTRACT]
ISSN:0146-6615
1096-9071
DOI:10.1002/jmv.23442