Hepatitis C virus NS3/4A protease blocks IL-28 production.
Type I interferons (IFNs), including IFN-α, -β, and -ω, play a critical role in innate immune responses against viral infection. IFN-λ, including IL-29, IL-28A, and IL-28B, recently identified as a new subfamily of IFN named type III IFN, has also been demonstrated to suppress virus replication in vitro and in vivo. However, the molecular mechanisms that regulate the induction of type III IFNs during viral infection remain elusive. Here, we demonstrate that IL-28 (IFN-λ 2/3) IFN production, similar to type I IFN, represents a primary and direct host response to HCV genomic RNA transfection. IL-28 (IFN-λ2/3) induction by HCV genomic RNA was dependent upon the activation of NF-κB and IRF3. We identified a minimal IL-28 promoter region consisting of putative NF-κB and IRF3-binding sites. Furthermore, we showed that HCV infection can inhibit HCV genomic RNA-induced IL-28 expression, and that the viral NS3/4A protease activity was responsible for this inhibitory effect. Our results present important evidence for the control of type III IFN response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.
Unit of Viral Hepatitis, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Qiang
Q
Ding
Bing
B
Huang
Jie
J
Lu
Yong-Jun
YJ
Liu
Jin
J
Zhong
D020413:3' Untranslated Regions; D001665:Binding Sites; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016679:Genome, Viral; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology; D000095022:Interferon Lambda; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases
D020413:3' Untranslated Regions; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D007372:Interferons; D007378:Interleukins; D016328:NF-kappa B; D012367:RNA, Viral; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494232:IRF3 protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases; C452820:RIGI protein, human