Double-stranded RNA-induced interferon-beta and inflammatory cytokine production modulated by hepatitis C virus serine proteases derived from patients with hepatic diseases.
We previously demonstrated that hepatitis C virus (HCV) serine protease NS3-4A was unable to cleave TRIF (adaptor protein of Toll-like receptor 3), resulting in a lack of suppression of the TRIF-mediated pathway, whereas NS3-4A cleaved Cardif (adaptor protein of retinoic acid-inducible gene I or melanoma differentiation-associated gene-5), resulting in an interruption of the Cardif-mediated pathway in non-neoplastic human hepatocyte PH5CH8 cells. To elucidate these observations, we examined the cleavage potential of NS3-4A for TRIF in PH5CH8 cells, genome-length HCV RNA-replicating O cells, and HCV-infected cells, and we demonstrated that NS3-4A lacked the ability to cleave endogenous TRIF, regardless of HCV strains derived from patients with different stages of hepatic disease. Furthermore, we demonstrated that inflammatory cytokine production by NF-kappaB activation via the TRIF-mediated pathway also remained unsuppressed by NS3-4A. These results suggest that the inhibitory effects of NS3-4A on antiviral signaling pathways are limited to the Cardif-mediated pathway in human hepatocytes.
Dansako
Hiromichi
H
Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Ikeda
Masanori
M
Ariumi
Yasuo
Y
Wakita
Takaji
T
Kato
Nobuyuki
N
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D002460:Cell Line; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology / Q000821:virology; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000276:immunology / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D033942:Adaptor Proteins, Vesicular Transport; D016899:Interferon-beta; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C470409:TICAM1 protein, human