biostudies-literatureLi JCSP VANIAID NIH HHSe00385-13https://www.ebi.ac.uk/biostudies/studies/S-EPMC3684836biostudies-literatureUnknown4(3)The type I interferon (IFN) signaling pathway restricts infection of many divergent families of RNA and DNA viruses by inducing hundreds of IFN-stimulated genes (ISGs), some of which have direct antiviral activity. We screened 813 short hairpin RNA (shRNA) constructs targeting 245 human ISGs using a flow cytometry approach to identify genes that modulated infection of West Nile virus (WNV) in IFN-β-treated human cells. Thirty ISGs with inhibitory effects against WNV were identified, including several novel genes that had antiviral activity against related and unrelated positive-strand RNA viruses. We also defined one ISG, activating signal cointegrator complex 3 (ASCC3), which functioned as a negative regulator of the host defense response. Silencing of ASCC3 resulted in upregulation of mumBioA short hairpin RNA screen of interferon-stimulated genes identifies a novel negative regulator of the cellular antiviral response.PMC3684836HHSN272200900041CR01 AI104972HHSN272200900041CU19U19 AI083019U54 AI081680AI083019Ding SCDiamond MSGale MLi JCho HChung BCChanda SKfalseA short hairpin RNA screen of interferon-stimulated genes identifies a novel negative regulator of the cellular antiviral response.The type I interferon (IFN) signaling pathway restricts infection of many divergent families of RNA and DNA viruses by inducing hundreds of IFN-stimulated genes (ISGs), some of which have direct antiviral activity. We screened 813 short hairpin RNA (shRNA) constructs targeting 245 human ISGs using a flow cytometry approach to identify genes that modulated infection of West Nile virus (WNV) in IFN-β-treated human cells. Thirty ISGs with inhibitory effects against WNV were identified, including several novel genes that had antiviral activity against related and unrelated positive-strand RNA viruses. We also defined one ISG, activating signal cointegrator complex 3 (ASCC3), which functioned as a negative regulator of the host defense response. Silencing of ASCC3 resulted in upregulation of mu2013-01-01T00:00:00Z2013 Jun2026-05-29T15:43:57.136Z2026-05-17T03:07:40.745ZS-EPMC36848362378107110.1128/mBio.00385-13