|A functional genomic screen reveals novel host genes that mediate interferon-alpha′s effects against hepatitis C virus|
|Zhao, Hong1,2; Lin, Wenyu1; Kumthip, Kattareeya1; Cheng, Du1; Fusco, Dahlene N.1; Hofmann, Oliver; Jilg, Nikolaus1; Tai, Andrew W.3; Goto, Kaku1; Zhang, Leiliang1; Hide, Winston4; Jang, Jae Young1; Peng, Lee F.1; Chung, Raymond T.1|
|关键词||HCV IFN-alpha siRNA SART1 U4/U6.U5tri-snRNP|
|刊名||JOURNAL OF HEPATOLOGY|
|WOS标题词||Science & Technology|
|类目[WOS]||Gastroenterology & Hepatology|
|研究领域[WOS]||Gastroenterology & Hepatology|
|关键词[WOS]||KINASE PATHWAY ; TRI-SNRNP ; REPLICATION ; EXPRESSION ; RIBAVIRIN ; NETWORK ; CULTURE|
Background & Aims: The precise mechanisms by which IFN exerts its antiviral effect against HCV have not yet been elucidated. We sought to identify host genes that mediate the antiviral effect of IFN-alpha by conducting a whole-genome siRNA library screen.
Methods: High throughput screening was performed using an HCV genotype 1b replicon, pRep-Feo. Those pools with replicate robust Z scores >= 2.0 entered secondary validation in full-length OR6 replicon cells. Huh7.5.1 cells infected with JFH1 were then used to validate the rescue efficacy of selected genes for HCV replication under IFN-alpha treatment.
Results: We identified and confirmed 93 human genes involved in the IFN-alpha anti-HCV effect using a whole-genome siRNA library. Gene ontology analysis revealed that mRNA processing (23 genes, p = 2.756e-22), translation initiation (nine genes, p = 2.42e-6), and IFN signaling (five genes, p = 1.00e-3) were the most enriched functional groups. Nine genes were components of U4/U6.U5 tri-snRNP. We confirmed that silencing squamous cell carcinoma antigen recognized by T cells (SART1), a specific factor of tri-snRNP, abrogates IFN-alpha′s suppressive effects against HCV in both replicon cells and JFH1 infectious cells. We further found that SART1 was not IFN-alpha inducible, and its anti-HCV effector in the JFH1 infectious model was through regulation of interferon stimulated genes (ISGs) with or without IFN-alpha.
Conclusions: We identified 93 genes that mediate the anti-HCV effect of IFN-alpha through genome-wide siRNA screening; 23 and nine genes were involved in mRNA processing and translation initiation, respectively. These findings reveal an unexpected role for mRNA processing in generation of the antiviral state, and suggest a new avenue for therapeutic development in HCV. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
|项目编号||81170386 ; A1082630 ; DK078772 ; DK088951 ; UL1 RR 025758 ; U54 A1057159|
|资助机构||National Natural Science Foundation of China ; research foundation of Peking University First Hospital ; Chinese Scholarship Council ; NIH-MGH Center for Human Immunology Pilot/Feasibility Study ; National Institutes of Health ; NERCE ; Harvard Clinical and Translational Science Center|
|作者单位||1.Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Gastrointestinal Unit, Boston, MA 02114 USA|
2.Peking Univ, Hosp 1, Dept Infect Dis, Beijing 100034, Peoples R China
3.Univ Michigan Hlth Syst Ann Arbor, Dept Med, Ann Arbor, MI 48105 USA
4.Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA
|Zhao, Hong,Lin, Wenyu,Kumthip, Kattareeya,et al. A functional genomic screen reveals novel host genes that mediate interferon-alpha′s effects against hepatitis C virus[J]. JOURNAL OF HEPATOLOGY,2012,56(2):326-333.|
|APA||Zhao, Hong.,Lin, Wenyu.,Kumthip, Kattareeya.,Cheng, Du.,Fusco, Dahlene N..,...&Chung, Raymond T..(2012).A functional genomic screen reveals novel host genes that mediate interferon-alpha′s effects against hepatitis C virus.JOURNAL OF HEPATOLOGY,56(2),326-333.|
|MLA||Zhao, Hong,et al."A functional genomic screen reveals novel host genes that mediate interferon-alpha′s effects against hepatitis C virus".JOURNAL OF HEPATOLOGY 56.2(2012):326-333.|