Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_307


Historical Background

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.

IRF5 is generally localized to the cytoplasm of a cell in an inactivate state, and undergoes nuclear translocation upon “activation.” The exact mechanism of IRF5 nuclear translocation in response to a given stimuli has not been fully elucidated but generally requires post-translational modification and homodimerization or heterodimerization with other IRF family members and proteins (Barnes et al. 2002; Cheng et al. 2006). IRF5 contains two functional nuclear localization signals (NLS), one in the amino-terminus and the other in the carboxyl-terminus of the protein (Barnes et al. 2002). IRF5 also contains a nuclear export signal (NES) that has been shown to regulate the dynamic shuttling of cellular IRF5 between the cytoplasm and the nucleus (Cheng et al. 2006). The molecular pathways leading to IRF5 activation include virus infection (Barnes et al. 2001, 2002), Toll-like receptor (TLR) signaling (Schoenemeyer et al. 2005; Takaoka et al. 2005), DNA damage (Hu et al. 2005), and death receptor signaling (Hu and Barnes 2009). Current data support the phosphorylation of IRF5 within the carboxyl-terminal autoinhibitory domain (Barnes et al. 2002; Chen et al. 2008) resulting in activation. The structural and functional domains of the IRF5 polypeptide are shown in Fig. 1.
IRF5, Fig. 1

Domain structure of IRF5. Structural and functional domains involved in DNA binding, subcellular localization, posttranslational modification, and interaction with other proteins are shown. DNA binding domain is shown by the gray box containing the tryptophan repeat, the white circle represents a proline-rich region, the IAD (IRF activation domain) illustrates the protein-interacting domain, the circled P represents the carboxyl-terminal region, where phosphorylation occurs with residues shown below. Top two sequences are nuclear localization signals (NLS), bottom first sequence (behind the DNA binding domain) represents the nuclear export signal (NES)

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

In addition to coordinating the expression of type I IFNs in response to virus infection, IRF5 regulates the expression of a number of other cytokines and chemokines. Virus-infected B cells generated to overexpress human IRF5 were found to express a number of chemokines important for the recruitment of T lymphocytes to sites of inflammation such as RANTES, macrophage inflammatory protein (MIP1α) and monocyte chemoattractant protein 1 (MCP1) (Barnes et al. 2002). Data from microarray analyses further supported these findings and demonstrated a distinct role for IRF5 in the regulation of antiviral and early inflammatory genes (Barnes et al. 2004). Subsequently, IRF5 was shown to be a central mediator of TLR signaling (Schoenemeyer et al. 2005; Takaoka et al. 2005). Members of the TLR family are essential recognition and signaling components of mammalian antiviral host defense. Studies in both humans and mice reveal the critical role that IRF5 plays in the gene induction program activated by TLR4, TLR7, and TLR9 (Schoenemeyer et al. 2005; Takaoka et al. 2005) (Fig. 2). In hematopoietic cells from mice deficient in the irf5 gene (irf5 / mice), the induction of cytokines interleukin 6 (IL6), IL12, TNFα, and IFNα by various TLR ligands was severely impaired, along with type I IFNs in response to virus infection (Takaoka et al. 2005; Paun et al. 2008). In human dendritic cells, IRF5 was shown to be required for late-phase TNF secretion through its direct and indirect binding to the TNF promoter (Krausgruber et al. 2010). While the mechanism of IRF5-mediated gene induction via virus is not well understood, induction by TLR ligands includes interaction and activation by MyD88, TRAF6 and TBK1 (Takaoka et al. 2005).
IRF5, Fig. 2

Role of IRF5 in TLR signaling. IRF5 interacts with MyD88, TRAF6, and TBK1 in response to TLR7 and 9 activation. IRF5 becomes phosphorylated, homodimerizes, and translocates to the nucleus where it induces proinflammatory cytokine expression

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 expression and alternative splicing are significantly upregulated in primary blood cells of SLE patients compared to healthy donors; enhanced transcript and protein levels are associated with an SLE risk haplotype suggesting a functional role for IRF5 in disease pathogenesis (Feng et al. 2010). Important insight on the potential function of IRF5 in SLE was gained by demonstrating an association between serum IFNα activity and IRF5 risk haplotype in SLE patients (Niewold et al. 2008); however, no direct evidence in humans has shown that the observed upregulation of IRF5 expression in SLE patients causes enhanced IFN production. Recent studies in mice have begun to elucidate how the dysregulation of IRF5 expression, and therefore function, may alter disease pathogenesis. Mice that produce IFNα, IFNβ, and IL6 in response to sera or IgG-RNA IC from lupus patients were shown to be tlr7, irf5, and irf7 dependent (Yasuda et al. 2007). Additional data revealed that irf5 is required for lupus development and autoantibody production in the FcγRIIB / Yaa and FcγRIIB / murine lupus models; however, no mechanism was provided (Richez et al. 2010). Subsequently, wild-type (irf5 +/+ ) and irf5 / mice injected with pristane oil, which typically induces development of features characteristic of human SLE, was found to markedly reduce IgG glomerular deposits and antinuclear antibodies, and lack of IgG2a autoantibody secretion in irf5 / mice (Savitsky et al. 2010). Data support that IRF5 is responsible for the secretion of pathogenic IgG2a antibodies through class-switch recombination of the γ2a locus and intimates a critical role for IRF5 in B cell activation and/or responses to pathogens (Savitsky et al. 2010) (Fig. 3).
IRF5, Fig. 3

Role of IRF5 in B cell function associated with lupus pathogenesis. TLR7 and 9 are thought to signal in response to SLE immune complexes resulting in pathogenic autoantibody production. The dysregulation of IRF5 expression in SLE affects autoantibody production by altering B cell differentiation and/or class-switch recombination

IRF5 in Cancer and as a Mediator of Apoptosis

Several lines of evidence support the notion that IRF5 is a candidate tumor suppressor gene. IRF5 expression is absent in a variety of immortalized tumor cell lines of hematologic malignancies (Barnes et al. 2001) and was shown to be a direct target of the tumor suppressor p53 (Mori et al. 2002). Analyses of IRF5 expression in primary mononuclear cells from healthy donors and patients with acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and acute monocytic leukemia (AML) confirmed a loss of IRF5 expression in cancers of hematologic origin (Barnes et al. 2003). Overexpression of IRF5 in a B cell lymphoma lacking functional p53 demonstrated for the first time the ability of IRF5 to recapitulate p53 tumor suppressor function (Barnes et al. 2003). Ectopic overexpression of IRF5 inhibited colony formation on soft agar and in vivo tumor cell growth in athymic nude mice (Mori et al. 2002; Barnes et al. 2003). In addition, IRF5 overexpression induced a G2/M cell cycle arrest and apoptosis by targeting genes with these functions (Barnes et al. 2003). Later studies in p53-deficient tumor cell lines demonstrated that IRF5 could sensitize them to DNA damage–induced apoptosis (Hu et al. 2005). Examination of the molecular mechanism(s) for sensitization revealed that DNA damage activated IRF5 by posttranslational modification resulting in nuclear translocation and induction of specific target genes (Hu et al. 2005). Data in irf5 / mice have corroborated these findings in human cells demonstrating that loss of irf5 makes cells resistant to DNA damage–induced apoptosis (Yanai et al. 2007). Furthermore, evidence is provided for its tumor suppressor function since irf5 / mice are predisposed to tumorigenic transformation (Yanai et al. 2007). While the exact DNA damage–induced signaling pathway that IRF5 mediates is not known, studies in mice and humans support that it is acting on a pathway distinct from p53 (Fig. 4) (Hu et al. 2005; Yanai et al. 2007).
IRF5, Fig. 4

IRF5 signals independent of p53 in response to DNA damage. DNA-PK is the candidate kinase for IRF5 activation in response to DNA damage induced by the chemotherapeutic agent Irinotecan (CPT-11). IRF5 target genes are shown, in addition to some known p53 target genes

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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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyNew Jersey Medical School-University Hospital Cancer Center, University of Medicine and Dentistry of New JerseyNewarkUSA