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Abstract

Interferon-induced transmembrane protein 3 (IFITM3) potently inhibits entry of diverse enveloped viruses by trapping the viral fusion at a hemifusion stage, but the underlying mechanism remains unclear. Here, we show that recombinant IFITM3 reconstituted into lipid vesicles induces negative membrane curvature and that this effect maps to its small amphipathic helix (AH). We demonstrate that AH (i) partitions into lipid-disordered domains where IAV fusion occurs, (ii) induces negative membrane curvature, and (iii) increases lipid order and membrane stiffness. These effects on membrane properties correlate with the fusion-inhibitory activity, as targeting the ectopically expressed AH peptide to the cytoplasmic leaflet of the cell plasma membrane diminishes IAV–cell surface fusion induced by exposure to acidic pH. Our results thus imply that IFITM3 inhibits the transition from hemifusion to full fusion by imposing an unfavorable membrane curvature and increasing the order and stiffness of the cytoplasmic leaflet of endosomal membranes. Our findings reveal a universal mechanism by which cells block entry of diverse enveloped viruses.