The transcription factor interferon regulatory factor 5 (IRF5) is one of the newer members of the IRF family to be characterized. All cellular family members share a region of homology in the amino-terminus, encompassing a highly conserved DNA binding domain consisting of five tryptophan repeats. By crystallography, this region has been shown to bind to conserved elements, termed “interferon (IFN)-stimulated response elements” (ISREs), in the promoters of target genes (Chen et al. 2008) thereby exerting the biological effects of IRF5. Given the nomenclature of this family, it is not surprising that the first function of IRF5 to be recognized was its ability to regulate type I IFN gene expression (Barnes et al. 2001). However, unlike other IRF family members, such as IRF3 and IRF7, the activity of IRF5 is regulated in a virus-specific manner leading to the induction of distinct IFNA genes (Barnes et al. 2001).
Regulation of IRF5 Biological Function
IRF5 is expressed primarily in human lymphoid tissues including the spleen, lymph nodes, peripheral blood lymphocytes, and bone marrow; low levels have been detected in the thymus and skeletal muscle (Barnes et al. 2001). High levels of IRF5 are constitutively expressed in purified immune cell subpopulations of activated B cells, natural killer cells, monocytes, plasmacytoid dendritic cells (PDC), and monocyte-derived dendritic cells (MDDC), suggesting an important role for IRF5 in the innate immune response (Mancl et al. 2005). Expression of IRF5 can also be detected in other cell types after stimulation with type I IFN or other inducers.
Human IRF5 exists as multiple alternatively spliced variants whose regulation is controlled at least in part by the presence of two functional promoters (Mancl et al. 2005). A number of these splice variants encode for functional polypeptides that have distinct cell type–specific expression, cellular localization, and biological function (Mancl et al. 2005). IRF5 expression may also be subject to regulation by hypermethylation as it contains a large CpG-rich island upstream of these promoters and has been shown to be regulated by hypermethylation in hepatocellular carcinoma tissues (Shin et al. 2010).
Role of IRF5 in the Innate Immune Response
IRF5 as an SLE Susceptibility Gene
Using the genome-wide association approach, multiple laboratories have identified and confirmed IRF5 gene variants with strong statistical association to SLE susceptibility (Kozyrev and Alarcon-Riquelme 2007). SLE is a complex systemic autoimmune disorder characterized by enhanced IFN production, loss of immune tolerance to self-antigens, persistent production of pathogenic autoantibodies, complement activation, immune complex (IC) deposition, inflammation, and end-organ damage. Identification of the IRF5 gene in the susceptibility to develop SLE has marked an important breakthrough in the understanding of SLE pathogenesis since it has provided the first evidence that both the type I IFN and TLR signaling pathways are involved in disease pathogenesis. Association has now been convincingly replicated in SLE patients from multiple populations and distinct IRF5 haplotypes that confer either susceptibility to (risk), or protection from, SLE in persons of varying ethnic ancestry have been identified (Kozyrev and Alarcon-Riquelme 2007). Genetic polymorphisms in the IRF5 gene are thought to alter IRF5 expression and/or lead to the expression of several unique isoforms (Kozyrev and Alarcon-Riquelme 2007).
Role of IRF5 in SLE Pathogenesis
IRF5 in Cancer and as a Mediator of Apoptosis
IRF5 has also been shown to regulate apoptosis in response to death receptor ligands Fas and TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) thus supporting its critical role in the apoptotic response (Couzinet et al. 2008; Hu and Barnes 2009). While the mechanism of IRF5-mediated Fas-induced cell death is unknown, but appears to be cell type–specific (Couzinet et al. 2008), the mechanism of IRF5-mediated TRAIL-induced apoptosis has been worked out and supports the mechanism requiring IRF5 activation by post-translational modification and nuclear translocation (Hu and Barnes 2009).
IRF5 is a critical mediator of the cellular response to extracellular stressors including virus, DNA damage, pathogenic stimuli (i.e., TLR ligands), and death ligands. IRF5 functions downstream of these signaling pathways thereby providing a mechanism of cellular protection in multiple cell types (i.e., immune cells, fibroblasts, epithelial cells). Once activated by posttranslational modification, IRF5 translocates to the nucleus where it acts as a transcription factor regulating the expression of genes involved in innate immunity, cell growth regulation, and apoptosis. Given that IRF5 expression has been found to be dysregulated in a variety of cancers (most prominently in hematologic malignancies), combined with the fact that mice lacking irf5 are susceptible to oncogene-induced tumor transformation and resistant to DNA damage–induced apoptosis, provides convincing support for its role as a new tumor suppressor gene. The fact that IRF5 mediates a DNA damage–induced signaling pathway that is distinct from p53 (Fig. 4) suggests that therapeutic strategies targeting this pathway will be useful for the treatment of p53-deficient cancers. Identifying the kinase(s) responsible for IRF5 activation in response to DNA damage, along with determining the p53-independent and IRF5-dependent signaling pathway induced by DNA damage, will be of critical importance for the design of agents that can upregulate and/or activate this pathway. Additionally, data support the inhibition of IRF5 activation and/or signaling in autoimmune disease. IRF5 expression is significantly upregulated in SLE patients; therefore, the design of therapeutic agents targeting the inhibition of IRF5 signaling in autoimmune diseases should prove beneficial. The ultimate challenge will be finding a balance in turning on and off IRF5 signaling that will not compromise a patients risk for cancer and autoimmune disease.
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