title: Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response.
abstract: Viral infections activate cellular expression of type I interferons (IFNs). These responses are partly triggered by RIG-I and mediated by Cardif, TBK1, IKKepsilon and IRF-3. This study analysed the mechanisms of dsRNA-induced IFN responses in various cell lines that supported subgenomic hepatitis C virus (HCV) replication. Transfection of dsRNA into Huh7, HeLa and HEK293 cells induced an IFN expression response as shown by IRF-3 dimerization, whilst these responses were abolished in corresponding cell lines that expressed HCV replicons. Similarly, RIG-I-dependent activation of the IFN-stimulated response element (ISRE) was significantly suppressed by cells expressing the HCV replicon and restored in replicon-eliminated cells. Overexpression analyses of individual HCV non-structural proteins revealed that NS4B, as well as NS34A, significantly inhibited RIG-I-triggered ISRE activation. Taken together, HCV replication and protein expression substantially blocked the dsRNA-triggered, RIG-I-mediated IFN expression response and this blockade was partly mediated by HCV NS4B, as well as NS34A. These mechanisms may contribute to the clinical persistence of HCV infection and could constitute a novel antiviral therapeutic target.
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Tasaka
authors.affiliation: Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.|Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Itakura
authors.affiliation: Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Itsui
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sekine-Osajima
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishimura-Sakurai
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Cheng-Hsin
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Genetics, Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Yoneyama
authors.affiliation: Laboratory of Molecular Genetics, Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.affiliation: First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.affiliation: First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D015536:Down-Regulation; D016679:Genome, Viral; D016174:Hepacivirus / Q000737:chemistry / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000096:biosynthesis*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012093:Replicon; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; C437968:PLAAT4 protein, human; D018168:Receptors, Retinoic Acid; D017361:Viral Nonstructural Proteins; D007372:Interferons