Hepatitis C virus NS5B delays cell cycle progression by inducing interferon-beta via Toll-like receptor 3 signaling pathway without replicating viral genomes.
To clarify the pathogenesis of hepatitis C virus (HCV), we have studied the effects of HCV proteins using human hepatocytes. Here, we found that HCV NS5B, an RNA-dependent RNA polymerase, delayed cell cycle progression through the S phase in PH5CH8 immortalized human hepatocyte cells. Since treatment with anti-interferon (IFN)-beta neutralizing antibody restored the cell cycle delay, IFN-beta was deemed responsible for the cell cycle delay in NS5B-expressing PH5CH8 cells. The induction of IFN-beta and the cell cycle delay were overridden by the down-regulation of Toll-like receptor 3 (TLR3) through RNA interference in NS5B-expressing PH5CH8 cells. Moreover, the NS5B full form was required for the cell cycle delay, the induction of IFN-beta, and the activation of the IFN-beta signaling pathway. Our findings revealed that NS5B induced IFN-beta through the TLR3 signaling pathway in immortalized human hepatocytes even without replicating viral genomes.
Naka
Kazuhito
K
Department of Molecular Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Dansako
Hiromichi
H
Kobayashi
Naoya
N
Ikeda
Masanori
M
Kato
Nobuyuki
N
D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D016174:Hepacivirus / Q000472:pathogenicity*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D034622:RNA Interference; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase
D016899:Interferon-beta; D051196:Toll-Like Receptor 3; D017361:Viral Nonstructural Proteins; C495344:TLR3 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase