title: Roles of unphosphorylated ISGF3 in HCV infection and interferon responsiveness.
abstract: Up-regulation of IFN-stimulated genes (ISGs) is sustained in hepatitis C virus (HCV)-infected livers. Here, we investigated the mechanism of prolonged ISG expression and its role in IFN responsiveness during HCV infection in relation to unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), recently identified as a tripartite transcription factor formed by high levels of IFN response factor 9 (IRF9), STAT1, and STAT2 without tyrosine phosphorylation of the STATs. The level of U-ISGF3, but not tyrosine phosphorylated STAT1, is significantly elevated in response to IFN-λ and IFN-β during chronic HCV infection. U-ISGF3 prolongs the expression of a subset of ISGs and restricts HCV chronic replication. However, paradoxically, high levels of U-ISGF3 also confer unresponsiveness to IFN-α therapy. As a mechanism of U-ISGF3-induced resistance to IFN-α, we found that ISG15, a U-ISGF3-induced protein, sustains the abundance of ubiquitin-specific protease 18 (USP18), a negative regulator of IFN signaling. Our data demonstrate that U-ISGF3 induced by IFN-λs and -β drives prolonged expression of a set of ISGs, leading to chronic activation of innate responses and conferring a lack of response to IFN-α in HCV-infected liver.
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea;
authors.forename: Pil Soo
authors.initials: PS
authors.lastname: Sung
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: HyeonJoo
authors.initials: H
authors.lastname: Cheon
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea;
authors.forename: Chung Hwan
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea;
authors.forename: Seon-Hui
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Pathology, Pusan National University Hospital and Pusan National University, Busan 602-739, Republic of Korea;
authors.forename: Do Youn
authors.initials: DY
authors.lastname: Park
authors.affiliation: Department of Surgery, Pusan National University Hospital and Pusan National University, Busan 602-739, Republic of Korea;
authors.forename: Hyung-Il
authors.initials: HI
authors.lastname: Seo
authors.affiliation: Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea;
authors.forename: Su-Hyung
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-040, Republic of Korea.
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; ecshin@kaist.ac.kr starkg@ccf.org.
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.affiliation: Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea; ecshin@kaist.ac.kr starkg@ccf.org.
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
mesh_terms: D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D016174:Hepacivirus; D006526:Hepatitis C / Q000276:immunology / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D007372:Interferons / Q000276:immunology*; D016086:Lentivirus / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000821:virology; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014443:Tyrosine / Q000737:chemistry; D043222:Ubiquitin Thiolesterase
chemical_list: C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D014443:Tyrosine; D007372:Interferons; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase
keywords: U-ISGF3; hepatitis C virus; interferon; interferon-stimulated genes