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.

Our study focused on IFITM3 protein, which shares a relatively high sequence homology and subcellular distribution with IFITM2. Although we have not addressed the mechanism of action of the plasma membrane-resident IFITM1, the published literature and our findings support the notion that this protein also acts by a proximity-based mechanism. We thus speculate that all members of the IFITM family accumulate at the sites of fusion of sensitive viruses and block the formation of a fusion pore. The current study provided strong evidence that LASV escapes IFITM3 restriction by entering through alternative endocytic pathways, but has not addressed whether other IFITM-resistant viruses, such as Junin virus or MLV, employ the same strategy to infect IFITM-expressing cells. Future studies addressing this question will help generalize the escape mechanism discovered in this work and may suggest strategies to increase the potency of IFITMs by modulating their intracellular trafficking.