▪ Abstract The interferon system is the first line of defense against viral infection in mammals. This system is designed to block the spread of virus infection in the body, sometimes at the expense of accelerating the death of the infected cells. As expected of potent cytokines, in addition to their antiviral effects, interferons have profound effects on many aspects of cell physiology. All these actions of interferons are mediated by hundreds of interferon-induced proteins that are usually not synthesized in resting cells. Interferons induce their synthesis by activating the Jak-STAT pathways, a paradigm of cell signaling used by many cytokines and growth factors. Surprisingly, some of the same genes can also be induced directly by viruses and double-stranded RNA, a common viral by-product. Some of the interferon-induced proteins have novel biochemical properties and some are inactive as such but can be activated by double-stranded RNA produced during virus infection. Finally, almost all viruses have evolved mechanisms to evade the interferon system by partially blocking interferon synthesis or interferon action. Thus, in nature interferons and viruses maintain an equilibrium that allows regulated viral replication.

A major component of the protective antiviral host defense is contributed by the intracellular actions of the proteins encoded by interferon-stimulated genes (ISGs); among these are the i nter f eron- i nduced proteins with t etratricopeptide repeats (IFITs), consisting of four members in human and three in mouse. IFIT proteins do not have any known enzyme activity. Instead, they inhibit virus replication by binding and regulating the functions of cellular and viral proteins and RNAs. Although all IFITs are comprised of multiple copies of the degenerate tetratricopeptide repeats, their distinct tertiary structures enable them to bind different partners and affect host-virus interactions differently. The recent use of Ifit knockout mouse models has revealed novel antiviral functions of these proteins and new insights into the specificities of ISG actions. This article focuses on human and murine IFIT1 and IFIT2 by reviewing their mechanisms of action, their critical roles in protecting mice from viral pathogenesis, and viral strategies to evade IFIT action.

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.

Upon infection with many RNA viruses, the cytoplasmic retinoic acid inducible gene‐I (RIG‐I) pathway activates the latent transcription factor IRF‐3, causing its nuclear translocation and the induction of many antiviral genes, including those encoding interferons. Here, we report a novel and distinct activity of IRF‐3, in virus‐infected cells, that induces apoptosis. Using genetically defective mouse and human cell lines, we demonstrated that, although both pathways required the presence of RIG‐I, IPS1, TRAF3 and TBK1, only the apoptotic pathway required the presence of TRAF2 and TRAF6 in addition. More importantly, transcriptionally inactive IRF‐3 mutants, such as the one missing its DNA‐binding domain, could efficiently mediate apoptosis. Apoptosis was triggered by the direct interaction of IRF‐3, through a newly identified BH3 domain, with the pro‐apoptotic protein Bax, their co‐translocation to the mitochondria and the resulting activation of the mitochondrial apoptotic pathway. Thus, IRF‐3 is a dual‐action cytoplasmic protein that, upon activation, translocates to the nucleus or to the mitochondrion and triggers two complementary antiviral responses of the infected cell. There is a [Have you seen ...?][1] (May 2010) associated with this Article. [1]: http://dx.doi.org/10.1038/emboj.2010.79

We report a new pathway of translation regulation that may operate in interferon‐treated or virus‐infected mammalian cells. This pathway is activated by P56, a protein whose synthesis is strongly induced by interferons or double‐stranded RNA. Using a yeast two‐hybrid screen, we identified the P48 subunit of the mammalian translation initiation factor eIF‐3 as a protein that interacts with P56. The P56–P48 interaction was confirmed in human cells by co‐immunoprecipitation assays and confocal microscopy. Gel filtration assays revealed that P56 binds to the large eIF‐3 complex that contains P48. Purified recombinant P56 inhibited in vitro translation of reporter mRNAs in a dose‐dependent fashion, and that inhibition was reversed by the addition of purified eIF‐3. In vivo, expression of transfected P56 or induction of the endogenous P56 by interferon caused an inhibition of overall cellular protein synthesis and the synthesis of a transfected reporter protein. As expected, a P56 mutant that does not interact with P48 and eIF‐3 failed to inhibit protein synthesis in vitro and in vivo.