biostudies-literatureDittmann MNCATS NIH HHSHoward Hughes Medical InstituteNIAID NIH HHSThe Francis Crick InstituteMedical Research CouncilPHS HHS631-643https://www.ebi.ac.uk/biostudies/studies/S-EPMC4328142biostudies-literatureUnknown160(4)Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPICellA serpin shapes the extracellular environment to prevent influenza A virus maturation.PMC4328142R01 AI09170710206MC_U117597139G0801822MR/K024752/1UL1 TR000043U54-AI057158U54 AI0571588UL1TR000043R01-AI091707U117597139Gilmore RHCrotta SBell KLWack ACasanova JLFlatley BHoffmann HHBieniasz PDWilson SJXiao JWScull MACiancanelli MRice CMDittmann MYu YfalseA serpin shapes the extracellular environment to prevent influenza A virus maturation.Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPI2015-01-01T00:00:00Z2015 Feb2026-05-29T15:34:24.178Z2019-03-27T01:45:13ZS-EPMC43281422567975910.1016/j.cell.2015.01.040