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

Harriet V Mears,Trevor R Sweeney

doi:10.1099/jgv.0.001149

Abstract

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.

Highlights

The interferon-induced proteins with tetratricopeptide repeats (IFITs) are a family of antiviral RNA-binding proteins, which are among the highest expressed genes during antiviral immune responses
While this movement was hypothesized to account for the increased affinity of the complex for cap0 mRNA, it is much smaller than the conformational change observed between 5 -ppp RNA bound and unbound forms of IFIT5
This brings IFIT2 and IFIT3 above their melting points, indicating that partial unfolding of the proteins is required to promote the formation of a heterocomplex, possibly by the exchange of N-terminal tetratricopeptide repeat (TPR)

Summary

INTRODUCTION

The interferon-induced proteins with tetratricopeptide repeats (IFITs) are a family of antiviral RNA-binding proteins, which are among the highest expressed genes during antiviral immune responses. In the structure of the partial IFIT1 : IFIT3 complex, the C terminus of IFIT1 is rotated towards the RNA-binding pocket by ~4 Å when compared to homodimeric IFIT1 [25] While this movement was hypothesized to account for the increased affinity of the complex for cap0 mRNA, it is much smaller than the conformational change observed between 5 -ppp RNA bound and unbound forms of IFIT5. In vitro-purified IFIT2 and IFIT3 only interact when heated to physiological temperatures [34] As described above, this brings IFIT2 and IFIT3 above their melting points, indicating that partial unfolding of the proteins is required to promote the formation of a heterocomplex, possibly by the exchange of N-terminal TPRs. The resultant IFIT2 : IFIT3 heterodimer is significantly more stable than either homodimer, and thermodynamically preferable. That IFIT3-dependent relocalization of JAB1 to the cytoplasm may promote this interaction with TYK2 to potentiate IFN signalling

A ROLE FOR IFIT2 IN INFLAMMATION

CONCLUSIONS