Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses.
The persistent nature of hepatitis C virus (HCV) infection suggests that HCV encodes proteins that enable it to overcome host antiviral responses. Toll-like receptor 3 (TLR3)-mediated signaling, which recognizes the double-stranded RNA that is produced during viral replication and induces type I interferons, including interferon beta (IFN-beta), is crucial to the host defense against viruses. Recent studies suggest that a TIR domain-containing adaptor protein, TRIF, and two protein kinases, TANK-binding kinase-1 (TBK1) and IkappaB kinase-epsilon (IKKepsilon), play essential roles in TLR3-mediated IFN-beta production through the activation of the transcriptional factor interferon regulatory factor 3 (IRF-3). We report that the HCV NS3 protein interacts directly with TBK1, and that this binding results in the inhibition of the association between TBK1 and IRF-3, which leads to the inhibition of IRF-3 activation. In conclusion, these results suggest the mechanisms of the inhibition of the innate immune responses of HCV infection by NS3 protein.
Otsuka
Motoyuki
M
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Japan.
Kato
Naoya
N
Moriyama
Masaru
M
Taniguchi
Hiroyoshi
H
Wang
Yue
Y
Dharel
Narayan
N
Kawabe
Takao
T
Omata
Masao
M
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development*; D006526:Hepatitis C / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D007372:Interferons / Q000235:genetics / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012093:Replicon / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D007372:Interferons; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C470409:TICAM1 protein, human; C403191:TBK1 protein, human