Interferon Regulatory Factors: Bridging Antiviral Defense, Growth Control, and Immunoregulation

Abstract

3 SINCE THEIR DISCOVERY IN 1957, interferons (IFN) have continuously played a central role in basic, applied, and clinical research as mediators of antiviral and antigrowth responses, as modulators of the immune response, and as therapeutic agents to combat viral diseases and cancer. IFN have served also as an important paradigm to investigate cytokine responses, signal transduction, and transcription control. Much of the information available on IFN gene regulation has derived from studies on the family of type I IFN genes, as well as the IFNstimulated genes (ISG), and has resulted in characterization of novel transcriptional proteins, common and unique signalling pathways leading to IFN and ISG activation, and the discovery of the IFN regulatory factors (IRF) and signal transducers and activators of transcription (Stat) families. IRF-1 and IRF-2 were originally identified as the transcriptional activator and repressor, respectively, of the type I IFN genes. The family has now expanded to include seven additional members: IRF-3 IRF-4 (Pip/LSIRF/ICSAT), IRF-5, IRF-6, IRF-7, IRF-8 (IFN consensus sequence binding protein [ICSBP]), and IRF-9 (ISG factor 3g/p48 [ISGF3g/p48]), and with the expansion has come the recognition of essential roles of IRF in immune regulation, growth control, and hematopoietic differentiation. All IRF share a high degree of homology in the N-terminal DNA binding domain and generally bind the DNA sequence GAAANNGAAANN. Variations in this canonical sequence, together with IRF interactions with other transcriptional partners, lead to the generation of transactivation and in some cases transrepression potential. Additional mechanisms allowing for differential gene regulation by IRF include cell type specificity, subcellular localization, and activator-specific phosphorylation events. The C-terminal portion of the IRF proteins is unique to each member and also contributes to the functional diversification of the IRF. The presence of virally encoded versions of IRF (vIRF) in the genome of human herpesvirus-8 (HHV-8), the virus responsible for Kaposi’s sarcoma, also illustrates the fact that viruses have evolved numerous mechanisms to evade the antiviral effect of IFN, including strategies to target the IRF. This Special Issue of the Journal of Interferon and Cytokine Research brings together many of the world’s leading researchers on this subject, and together they provide a comprehensive view of the range of activities controlled by the IRF family members. B. Barnes and colleagues provide an overview of the functions of the IRF in the innate immune response and immune evasive tactics of the vIRF homologs. Hauser’s group and Romeo’s group discuss the antiproliferative and tumorsuppressive properties of IRF-1. A. Battistini and colleagues describe the role of IRF-1 in regulating transcription from the HIV-1 long terminal repeat, and R. Pine illustrates a role for the IRF in the host response to mycobacterial infection. IRF-3 and IRF-7 are specifically involved in type I IFN gene expression. Viral infection causes the activation of an unknown kinase(s) and phosphorylation of both IRF-3 and IRF-7 in the cytoplasm. Virus-activated IRF-3/IRF-7 may undergo a conformational change that allows specific DNA binding to the type I IFN promoters, coactivator recruitment, and transcription of target genes. Several reviews cover this active area of research. M. Servant and colleagues discuss the structure and functional activation of IRF-3 and IRF-7. Fujita’s group provides a view of the regulatory phosphorylation events responsible for IRF-3 induction, and N.C. Reich reviews her studies on the mechanisms of nuclear import and export of IRF-3. Structure-function studies on the related IRF-7 factor are described by D. Levy and colleagues; L. Zhang and J.S. Pagano contribute a distinct view of IRF-7 from the perspective of the involvement of IRF-7 in control of Epstein-Barr virus transcription. A. Civas’s group describes the interactions of IRF-3 and IRF-7 with the IFN-a promoters. The lymphoid-myeloid-restricted members of the IRF family are also reviewed. S. Marecki and M. Fenton analyze the structure and function of IRF-4, with emphasis on the role of IRF-4 in macrophage-specific gene regulation, and A. Pernis addresses the functions of IRF-4 in T and B lymphoid cellspecific gene expression. From a different viewpoint, Y. Mamane and colleagues focus on the consequences of IRF-4 constitutive activation in human T cell leukemia virus (HTLV-1)infected lymphoid cells. T. Tamura and K. Ozato review their studies on the role of IRF-8/ICSBP in myeloid differentiation and the regulation of myeloid-specific target genes by IRF-8. B.-Z. Levi and colleagues review the functional protein-protein