biostudies-literatureFernbach SSwiss National Science Foundation110549https://www.ebi.ac.uk/biostudies/studies/S-EPMC8939003biostudies-literatureUnknown38(12)Host interferons (IFNs) powerfully restrict viruses through the action of several hundred IFN-stimulated gene (ISG) products, many of which remain uncharacterized. Here, using RNAi screening, we identify several ISG restriction factors with previously undescribed contributions to IFN-mediated defense. Notably, RABGAP1L, a Tre2/Bub2/Cdc16 (TBC)-domain-containing protein involved in regulation of small membrane-bound GTPases, robustly potentiates IFN action against influenza A viruses (IAVs). Functional studies reveal that the catalytically active TBC domain of RABGAP1L promotes antiviral activity, and the RABGAP1L proximal interactome uncovered its association with proteins involved in endosomal sorting, maturation, and trafficking. In this regard, RABGAP1L overexpression is sufficient to dCell reportsRestriction factor screening identifies RABGAP1L-mediated disruption of endocytosis as a host antiviral defense.PMC8939003182464Spieler EEHale BGFernbach SBusnadiego IKarakus ULkharrazi AStertz SfalseRestriction factor screening identifies RABGAP1L-mediated disruption of endocytosis as a host antiviral defense.Host interferons (IFNs) powerfully restrict viruses through the action of several hundred IFN-stimulated gene (ISG) products, many of which remain uncharacterized. Here, using RNAi screening, we identify several ISG restriction factors with previously undescribed contributions to IFN-mediated defense. Notably, RABGAP1L, a Tre2/Bub2/Cdc16 (TBC)-domain-containing protein involved in regulation of small membrane-bound GTPases, robustly potentiates IFN action against influenza A viruses (IAVs). Functional studies reveal that the catalytically active TBC domain of RABGAP1L promotes antiviral activity, and the RABGAP1L proximal interactome uncovered its association with proteins involved in endosomal sorting, maturation, and trafficking. In this regard, RABGAP1L overexpression is sufficient to d2022-01-01T00:00:00Z2022 Mar2026-05-30T16:48:34.011Z2024-11-13T07:41:58.349ZS-EPMC89390033532072110.1016/j.celrep.2022.110549