The ISG56/IFIT1 gene family

Abstract

The ISG56/IFIT1 family of genes is clustered on human chromosome 10 and is comprised of 4 members, ISG56/IFIT1, ISG54/IFIT2, ISG60/IFIT3, and ISG58/IFIT5, whose homologs are evolutionarily conserved from mammals to amphibians. While these genes are normally silent in most cell types, their transcription is strongly induced by interferons, virus infection, and molecular patterns such as double-stranded RNA or lipopolysaccharides. The encoded P56 family proteins are characterized by multiple repeats of tetratricopeptide repeat helix-turn-helix motifs mediating a variety of protein-protein interactions, which result in a multitude of effects on cellular and viral functions, such as translation initiation, virus replication, double-stranded RNA signaling, cell migration, and proliferation.

FIG. 1.

Chromosomal loci of the human and murine ISG56/IFIT1 family genes, depicting exon/intron structures, orientation of the open reading frames (arrowheads), and the positions and numbers of ISREs in the promoters (asterisks). Additional, uncharacterized IFIT genes are shown in gray. ISRE, interferon-stimulated response elements.

FIG. 2.

Pathways of ISG56 family gene induction, and functions of the encoded P56 family of proteins. Stimulation of innate immune receptors, especially IFNAR (IFN-α/β receptor) and the double-stranded RNA receptors TLR3 and RIG-I/MDA-5, induces transcription of ISG56 family genes via ISREs in their promoters. The respective protein products mediate inhibition of various cellular and viral processes by specific binding to effector proteins. IFN, interferon; IRF, IFN regulatory factors; TLR3, toll-like receptor 3. RIG-I, retinoic acid-inducible gene-I; MDA-5, melanoma differentiation-associated gene-5.

FIG. 3.

TPR motifs in homologs of the P56 family proteins of human and mouse (left), and predicted 3-dimensional structure of human P54, amino acids 23–471 (right). The PHYRE server (Kelley and Sternberg 2009) was used to predict 3-dimensional structure, observation with MolMol 2K.2 software (Koradi and others 1996). TPR, tetratricopeptide repeat.