| Project/Area Number |
24590960
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
OOKA Shinya 東京医科歯科大学, 医歯(薬)学総合研究科, 特任准教授 (90361691)
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| Co-Investigator(Kenkyū-buntansha) |
ASAHINA Yasuhiro 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692)
WATANABE Mamoru 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)
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| Co-Investigator(Renkei-kenkyūsha) |
SAKAMOTO Naoya 北海道大学, 医学研究科, 教授 (10334418)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | ＨＣＶ / インターフェロン / ＮＳ4Ｂ / ＩＬ28Ｂ / HCV / Cardif / IFNλ / IL-6 |
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| Outline of Final Research Achievements |
HCV infection blocks cellular IFN-mediated antiviral signaling through cleavage of Cardif by HCV-NS3/4A serine protease. Like NS3/4A, we found NS4B protein strongly blocks IFN-β production signaling mediated by RIG-I. IFN-β promoter reporter assay showed that IFN-β promoter activation induced by RIG-I or Cardif was significantly suppressed by both NS4B and NS3/4A, whereas STING-induced IFN-β activation was suppressed by NS4B but not by NS3/4A, suggesting that NS4B had a distinct point of interaction. Immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays demonstrated that NS4B specifically bound STING. Therefore, NS4B suppresses RIG-I-mediated IFN-β production signaling through a direct protein interaction with STING. Moreover, we reported over-expression of IL6, which is inhibitory molecule of type I/III IFN signaling, and IL28B (type III IFN) SNPs were closely associated with non-response to IFN-based anti-HCV therapy.
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