Fig. 1

The various mechanisms by which IFITM proteins may inhibit virus-cell fusion. a A simplified membrane topology model of IFITM3 is represented, with emphasis made on the amphipathic helix of hydrophobic domain 1, neighboring palmitoylated cysteine residues, and the transmembrane helix of hydrophobic domain 2. In this illustration, the amino-terminus faces the cytosol while the carboxy-terminus faces the ER/endosomal lumen or extracellular space, but other conformations may exist. b IFITM3 multimerization is important for antiviral activity and cell-based experiments indicate that IFITM3 augments membrane rigidity and instills positive curvature, as defined from the vantage of the cytosol. c IFITM3 may indirectly inhibit virus entry via an association with other membrane proteins, such as ZMPSTE24. Only three of seven transmembrane domains of ZMPSTE24 are indicated. d An effect of IFITM3 on the trafficking and/or function of the vacuolar ATPase (v-ATPase) has been reported, raising the possibility that IFITM3 indirectly inhibits virus entry by increasing endosomal acidity. e IFITM3 may influence the cholesterol content of endosomes, which has been shown to affect virus-cell fusion events. The actions of IFITM3 on virus entry and on cholesterol levels have been dissociated in several studies, but further impacts on membrane lipid content still await testing