IFITM proteins-cellular inhibitors of viral entry

Abstract

Interferon inducible transmembrane (IFITM) proteins are a recently discovered family of cellular anti-viral proteins that restrict the replication of a number of enveloped and non-enveloped viruses. IFITM proteins are located in the plasma membrane and endosomal membranes, the main portals of entry for many viruses. Biochemical and membrane fusion studies suggest IFITM proteins have the ability to inhibit viral entry, possibly by modulating the fluidity of cellular membranes. Here we discuss the IFITM proteins, recent work on their mode of action, and future directions for research.

Figure 1

IFITM protein topology and domain organisation. Panel (a) Topological models for IFITM proteins. (I) Represents an initial model for the proteins as transmembrane molecules with both the N-terminal and C-terminal domains (NTD and CTD) extracellular and the conserved intracellular loop (CIL) facing the cytoplasm [33]. Subsequently, an alternative model (II) was proposed with the NTD, CTD and CIL all positioned intracellularly, and neither membrane domain (M1 and M2, blue and purple respectively) spanning the bilayer [31]. The most recent model (III) combines models I and II, positioning the NTD and CIL in the cytoplasm and the CTD extracellularly. Currently, the topology represented by III is only established for murine IFITM3 [32]. Panel (b) Linear representation of human IFITM1, 2 and 3 showing key amino acids. In all cases, modifications and functional activities have only been established with IFITM3, but conserved residues in IFITM1 and 2 are shown.

Figure 2

IFITM proteins inhibit virus entry at different stages of cell trafficking. Viruses enter cells by fusing with or penetrating a limiting cellular membrane. For most enveloped viruses fusion occurs either at the cell surface or, following uptake by endocytosis, from within endosomes. Acid-dependent viruses require acidification of the endosomal lumen by the membrane-associate vacuolar proton ATPase for fusion (shown in red). Trafficking through the endocytic system, from early to late endosomes, exposes virions to increasingly acidic environments. IFITM proteins (green) can inhibit entry and infection by a number of viruses that fuse/penetrate at the cell surface or from within endosomes. IFITM1 is expressed primarily at the cell surface, while IFITM2 and 3 are primarily intracellular. IFITM3 has been localised to endosomal compartments, but the distribution of IFITM2 still needs to be clearly established.