Interferon-induced transmembrane protein 3 blocks fusion of sensitive but not resistant viruses by partitioning into virus-carrying endosomes

Suddala, Krishna C.; Lee, Christine C.; Meraner, Paul; Marin, Mariana; Markosyan, Ruben M.; Desai, Tanay M.; Cohen, Fredric S.; Brass, Abraham L.; Melikyan, Gregory B.

The mechanism by which IFITMs inhibit fusion of most viruses, while sparing others, is not understood. We and others have shown that IFITM expression does not elevate the overall endosomal pH [15-19, 22, 30, 31] and, thus, should not block acid-triggered refolding of viral fusion proteins that initiate membrane fusion. Clues regarding the antiviral mechanisms of IFITMs come from their subcellular distribution which tend to correlate with IFITM's potency against different viruses. IFITM2 and -3 better restrict viruses entering from late endosomes, while IFITM1 tends to be more effective against viruses that are thought to fuse with the plasma membrane or with early endosomes (reviewed in [17] ). Indeed, expression of an IFITM3 mutant that redistributes the late endosome/lysosome-resident protein to the cell surface abolishes antiviral activity against IAV [32] . There are, however, exceptions to this rule. The fact that IFITM1 outperforms IFITM3 in restricting EBOV fusion [25] highlights the importance of cellular trafficking, as opposed to the steady state distribution, for antiviral activity. Also, a relatively weak IAV restriction exhibited by an IFITM1 chimera containing the N-terminal domain of IFITM3 that localizes to late endosomes suggests a role for other factors in addition to appropriate subcellular localization [21] .