IFITs: Emerging Roles as Key Anti-Viral Proteins

Abstract

Interferon-induced proteins with tetratricopeptide repeats (IFITs) are a family of proteins, which are strongly induced downstream of type I interferon signaling. The molecular mechanism of IFIT anti-viral activity has been studied in some detail, including the recently discovered direct binding of viral nucleic acid, the binding to viral and host proteins, and the possible involvement in anti-viral immune signal propagation. The unique structures of some members of the IFIT family have been solved to reveal an internal pocket for non-sequence-specific, but conformation- and modification-specific, nucleic acid binding. This review will focus on recent discoveries, which link IFITs to the anti-viral response, intrinsic to the innate immune system.

Keywords: IFIT; PAMPs; TPR; anti-viral immune response; innate immune system.

Figure 1

(A) The structures of human IFIT5 in complex with oligoA and human IFIT1 NTD in cartoon representation (PDB entries 4HOT and 4HOU). The subdomains identified in IFIT5 are color coded, and RNA is in red. (B) Cross-section of the complex of IFIT5 with oligoA, showing a narrow pocket that binds four nucleotides. (C) The structure of human IFIT2 (PDB entry 4G1T) colored according to the corresponding IFIT5 subdomains. Indicated are helices 7–9 that are swapped with the other protomer. (D) The Y156 of IFIT5 forms a hydrogen bond (dotted line) with the 2′-O of the first ribose (IFIT5 in complex with oligoU, PDB entry 4HOS). Metal ions are depicted as spheres (Red, Mg²⁺; Purple, Na²⁺).

Figure 2

IFITs, once upregulated due to IFN signaling, play various roles in blocking virus and host protein translation. IFIT1 can bind to the (A) 5′ of mis-modified RNA either which is 2′-O-unmethylated or has 5′PPP-RNA (features of foreign nucleic acid) vs. properly capped host mRNA. IFIT1, along with a complex of IFIT2 and IFIT3, can block translation of these nucleic acids. Multiple IFITs have been described to bind to various subunits of host (B) eIF3, a key component of mRNA translation. Though the target of eIF3 is properly processed mRNA, including host mRNA, IFIT1 may block translation cell-wide during virus infection. As well, IFIT1 can bind (C) a key virulence factor of HPV, helicase E1, and sequester it into the cytoplasm, thereby preventing virus replication.