| 抄録 |
Summaiy ： Hepatitis C virus （HCV） infection blocks cellular interferon （IFN）一mediated antiviral signalmgthrough cleavage of Cardif by HCV－NS3／4A serine protease． Like NS3／4ANS4B protei’n strongly blocksretinoic－acid－inducible protein I（RIG－1）一mediated IFN一βproduction signaling（Tasaka et al． J Gen Viro12007） ； howeverthe underlying molecular mechanisms are not well understood． Recentlythe stimulatorof interferon genes（ST工NG）was identified as an activator of RIG－I signaling． ST工NG possesses a structuralhomology domain with flaviviral NS4Bwhich suggest a direct protein－protein interactionln the presentstudywe investigated the molecular mechanisms by which NS 4 B targets RIG－1 induced and STINGmediated IFN－B production signaling． IFN－P promoter reporter assay showed that IFN－P promoter activa－tion induced by RIG－1 or Cardif was significantly suppressed by both NS4B and NS3／4Awhile STING－induced IFN－S activation was suppressed by NS4B but not by NS3／4Asuggesting that NS4B had a dis－tinct point of interaction． lmmunostaining showed that STING colocalized with NS4B in the endoplasmicreticulum． lmmunoprecipitation and bimolecular fluorescence complementation （BiFC） assays demon－strated that NS4B specifically bound STING． lntriguinglyNS4B expression blocked the protein interac－tion between STING and Cardifwhich is required for robust IFN－P activation． NS4B truncation assaysshowed that its N－terminuscontaining the STING－homology domainwas necessary for the suppression ofIFN－P promoter activation． NS4B suppressed residual IFN－P activation by an NS3／4A￡leaved Cardif （Car－dif1－508）suggesting that NS3／4A and NS4B may cooperate in the blockade of IFN一βproduction．Conclusion ： NS4B suppr／esses RIG－1－mediated IFN－P production signaling through a direct protein inter－action with STING． Disruption of that interaction may restore cellular antiviral responses and may consti－tute a novel therapeutic strategy against HCV． |
