Better together: the role of IFIT protein-protein interactions in the antiviral response

The interferon-induced proteins with tetratricopeptide repeats (IFITs) are a family of antiviral proteins conserved throughout all vertebrates. IFIT1 binds tightly to non-self RNA, particularly capped transcripts lacking methylation on the first cap-proximal nucleotide, and inhibits their translation by out-competing the cellular translation initiation apparatus. This exerts immense selection pressure on cytoplasmic RNA viruses to maintain mechanisms that protect their messenger RNA from IFIT1 recognition. However, it is becoming increasingly clear that protein-protein interactions are necessary for optimal IFIT function. Recently, IFIT1, IFIT2 and IFIT3 have been shown to form a functional complex in which IFIT3 serves as a central scaffold to regulate and/or enhance the antiviral functions of the other two components. Moreover, IFITs interact with other cellular proteins to expand their contribution to regulation of the host antiviral response by modulating innate immune signalling and apoptosis. Here, we summarize recent advances in our understanding of the IFIT complex and review how this impacts on the greater role of IFIT proteins in the innate antiviral response.