IFITM3 at the viral fusion-pore checkpoint: membrane energetics and entry-route-dependent outcomes

Interferon-induced transmembrane proteins (IFITMs) are small interferon-stimulated membrane proteins that can limit viral entry, but their effects depend on the virus, entry route, and experimental context. This Mini Review focuses on IFITM3 at the viral fusion-pore checkpoint, defined here as the transition at which hemifusion either proceeds to fusion-pore opening and viral-content release or stalls before productive entry. Work on influenza virus supports a model in which IFITM3 remodels late-endosomal membranes, prolongs or kinetically stabilizes hemifusion-like intermediates, and raises the activation-energy barrier to fusion-pore formation. Type I interferon signaling, host biological variation, IFITM3 polymorphisms, and post-translational regulation shape IFITM3 abundance and localization, whereas endolysosomal cholesterol homeostasis modifies the membrane environment encountered by incoming virions; whether altered sterol handling also changes IFITM3 turnover remains unresolved. The fusion-pore checkpoint is presented as a working model supported most directly by mechanistic studies of influenza A virus. Coronavirus studies and a Nipah virus entry model illustrate how IFITM phenotypes can shift among restriction, neutrality, and context-dependent support. We therefore interpret IFITM activity as an entry-route-dependent membrane phenotype and outline practical criteria for assigning these outcomes in viral entry studies.