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Limited suppression of the interferon‐β production by hepatitis C virus serine protease in cultured human hepatocytes
Author(s) -
Dansako Hiromichi,
Ikeda Masanori,
Kato Nobuyuki
Publication year - 2007
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2007.05942.x
Subject(s) - trif , interferon , mda5 , ns3 , signal transduction , signal transducing adaptor protein , interferon regulatory factors , biology , microbiology and biotechnology , innate immune system , irf3 , virology , receptor , toll like receptor , hepatitis c virus , virus , biochemistry , rna , rna interference , gene
Toll‐like receptors and RNA helicase family members [retinoic acid‐inducible gene I (RIG‐I) and melanoma differentiation associated gene‐5 (MDA5)] play important roles in the induction of interferon‐β as a major event in innate immune responses after virus infection. TRIF (adaptor protein of Toll‐like receptor 3)‐mediated and Cardif (adaptor protein of RIG‐I or MDA5)‐mediated signaling pathways contribute rapid induction of interferon‐β through the activation of interferon regulatory factor‐3 (IRF‐3). Previously, it has been reported that the hepatitis C virus NS3‐4A serine protease blocks virus‐induced activation of IRF‐3 in the human hepatoma cell line HuH‐7, and that NS3‐4A cleaves TRIF and Cardif molecules, resulting in the interruption of antiviral signaling pathways. On the other hand, it has recently been reported that non‐neoplastic human hepatocyte PH5CH8 cells retain robust TRIF‐ and Cardif‐mediated pathways, unlike HuH‐7 cells, which lack a TRIF‐mediated pathway. In the present study, we further investigated the effect of NS3‐4A on antiviral signaling pathways. Although we confirmed that PH5CH8 cells were much more effective than HuH‐7 cells for the induction of interferon‐β, we obtained the unexpected result that NS3‐4A could not suppress the interferon‐β production induced by the TRIF‐mediated pathway, although it suppressed the Cardif‐mediated pathway by cleaving Cardif at the Cys508 residue. Using PH5CH8, HeLa, and HuH‐7‐derived cells, we further showed that NS3‐4A could not cleave TRIF, in disagreement with a previous report describing the cleavage of TRIF by NS3‐4A. Taken together, our findings suggest that the blocking of the interferon production by NS3‐4A is not sufficient in HCV‐infected hepatocyte cells.