IFITM Genes, Variants, and Their Roles in the Control and Pathogenesis of Viral Infections

Abstract

Interferon-induced transmembrane proteins (IFITMs) are a family of small proteins that localize in the plasma and endolysosomal membranes. IFITMs not only inhibit viral entry into host cells by interrupting the membrane fusion between viral envelope and cellular membranes, but also reduce the production of infectious virions or infectivity of progeny virions. Not surprisingly, some viruses can evade the restriction of IFITMs and even hijack the antiviral proteins to facilitate their infectious entry into host cells or promote the assembly of virions, presumably by modulating membrane fusion. Similar to many other host defense genes that evolve under the selective pressure of microorganism infection, IFITM genes evolved in an accelerated speed in vertebrates and many single-nucleotide polymorphisms (SNPs) have been identified in the human population, some of which have been associated with severity and prognosis of viral infection (e.g., influenza A virus). Here, we review the function and potential impact of genetic variation for IFITM restriction of viral infections. Continuing research efforts are required to decipher the molecular mechanism underlying the complicated interaction among IFITMs and viruses in an effort to determine their pathobiological roles in the context of viral infections in vivo.

Keywords: IFITM; host susceptibility; interferon-induced transmembrane proteins; single nucleotide polymorphisms; viral infection.

FIGURE 1

IFITM gene structure. Human IFITM genes located in chromosome 11p15.5 are indicated, and the exons of immunity-related IFITM genes (IFITM1, IFITM2, and IFITM3) are indicated in blue color. The putative transcripts of IFITM2 and IFITM3 are also shown below. The transcription factor binding regions derived from UCSC Genome Browser are shown, which is verified by Chip-seq from the 161 proteins tested through ENCODE; GRCh37/hg19. Two red vertical lines across transcription factor binding sites represent the Influenza associated SNPs of rs12252 and rs34481144 with allele frequencies, respectively. N-terminally truncated IFITM3 isoform (Δ21 IFITM3) that is presumably generated by rs12252 is indicated.

FIGURE 2

Illustration of IFITM protein membrane topology. The three possible membrane topologies of IFITM3 (A) and six possible membrane topological forms of IFITM1 (B) are presented. The two transmembrane (or intramembrane) regions were highlighted in yellow.

FIGURE 3

Schematic diagram of IFITM1/3 topology and structural determinants essential for their modulation of viral entry. Five structural domains, including the N-terminal domain (NTD), amphipathic helix domain (AHD), intracellular loop (CIL), transmembrane domain (TMD), and C-terminal domain (CTD), are illustrated. Two membrane-associated domains (AHD and TMD) are embodied in light orange. In IFITM3, three hydrophilic residues (S61, N64, and T65) in amphipathic helix are labeled in violet. In NTD domain, ²⁰YEML²³ motif required for IFITM3 endocytosis are depicted in blue with red circle and ¹⁷PPNY²⁰ motif recruiting NEDD4 E3 ligase are shown in green. In CIL domain, ⁸¹SVKS⁸⁴ motif required for IFITM3 to inhibit IAV, DENV, and LLOV infection is indicated with purple circle. The residues with post-translational modification, including phosphorylation (Y20 and Y99 labeled with red circle), palmitoylation (C71, C72, and C105 marked with light blue), and ubiquitination (highlighted in orange), are indicated. In addition, two residues (F75 and F78) essential for oligomerization are marked with yellow. In IFITM1, C-terminal 12-aa residues critical for modulating human coronaviruses entry is indicated in blue, and ¹²²KR¹²³ dibasic motif constituted as IFITM1 sorting signal is depicted with red circle.