Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response.
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.
Tasaka
Megumi
M
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Sakamoto
Naoya
N
Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Itakura
Yoshie
Y
First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.|Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Nakagawa
Mina
M
Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.|Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Itsui
Yasuhiro
Y
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Sekine-Osajima
Yuko
Y
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Nishimura-Sakurai
Yuki
Y
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Chen
Cheng-Hsin
CH
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
Yoneyama
Mitsutoshi
M
Laboratory of Molecular Genetics, Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Fujita
Takashi
T
Laboratory of Molecular Genetics, Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Wakita
Takaji
T
Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
Maekawa
Shinya
S
First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.
Enomoto
Nobuyuki
N
First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.
Watanabe
Mamoru
M
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
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
D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; C437968:PLAAT4 protein, human; D018168:Receptors, Retinoic Acid; D017361:Viral Nonstructural Proteins; D007372:Interferons