Interferon-induced Ifit proteins: Their role in viral pathogenesis

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 interferon-induced proteins with tetratricopeptide repeats (IFITs), con-sisting of four members in human and three in mouse. IFIT proteins do not have any known enzyme activity. Instead, they in-hibit 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 mu-rine 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. Control of virus replication and pathogenesis in mammals de-pends on rapid detection of the pathogen by the infected cell and its ability tomount an immediate antiviral response to impair virus replication and to limit virus spread to neighboring cells. The antiviral response is triggered by the activation of specific signaling cascades leading to transcriptional induction of many antiviral genes, which encode intracellular proteins to protect th