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 most popular view of the mechanism of IFITM's antiviral activity is that these proteins create "tough membranes" that are not conducive to fusion [17, 18, 22] . Two principal models for membrane stiffening by IFITMs have been proposed-a direct effect on the membrane in the immediate proximity of these proteins [19, 25, [33] [34] [35] that could involve changing the membrane fluidity and/or curvature [22, 33, 35] , and an indirect effect through altering the lipid composition of endosomes [18] . Several lines of evidence support the proximity-based antiviral activity of IFITMs. First, as discussed above, there is a general correlation between the subcellular localization of IFITMs and their potency against viruses entering from distinct cellular compartments (reviewed in [17] ). Second, IFITM3-mediated restriction, but not restriction by the plasma membrane-resident IFITM1, can be bypassed by forcing virus fusion with the plasma membrane [25, 30] . Third, IFITM incorporation into the viral membrane effectively inhibits fusion/infectivity [34, [36] [37] [38] . On the other hand, IFITM3 has been reported to bind to and inhibit the function of vesicle-associated membrane protein-associated protein A (VAPA) [18] , the master regulator of endosome-ER lipid transport. While this model has been disputed by several groups [30, 35] , a recent study provided evidence for the antiviral effect of cholesterol accumulation in late endosomes/lysosomes and confirmed accumulation of cholesterol in these compartments upon IFITM3 expression [39] . It thus remains unclear whether IFITMs must be present at the sites of virus fusion to block virus entry or affect fusion indirectly, by dysregulating lipid transport or metabolism.