IRF5 The Outsider

Many members of the IRF family are important in innate and/or acquired immunity. Although they share a similar DNA-binding domain at their N-terminus, the different IRFs possess unique characteristics that result in unique protein-protein and protein-DNA interactions leading to unique functions. In most viral infections, dsRNA and LPS signaling can activate IRF3 and IRF7 (Doyle et al. 2002; Fitzgerald et al. 2003b; Kawai et al. 2001). In contrast, the activation of IRF5 is much more restricted. It occurs upon infection with Newcastle disease virus (NDV), VSV, and HSV (Barnes et al. 2002, 2003), while no effect has been detected following Sendai virus infection or dsRNA treatment (Schoenemeyer et al. 2005). Recently, an important role for IRF5 in TLR signaling has been emphasized (Schoenemeyer et al. 2005; Takaoka et al. 2005). IRF5 seems to be highly involved in the induction of proinflammatory cytokines, such as TNF-a, IL-12, and IL-6; in fact, their expression is severely impaired upon TLR4, 5, 7, and 9 triggering in various cells from IRF5 knockout mice (Takaoka et al. 2005). Putative IFN-stimulated response elements in the promoters of these inflammatory cytokines are suggested to bind IRF5. TLR7 and 8 triggering by the imidazoquinoline R-848 induced nuclear translocation of IRF5 in murine macrophages (Schoenemeyer et al. 2005), whereas IRF5 could not be activated by either the TLR3/TRIF pathway or upon SV infection. Data from several groups have shown that SV is detected by the recently identified RNA helicase RIG-I (Rothenfusser et al. 2005; Yoneyama et al. 2004).

Promoter Expression And Irf5

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Fig. 2 MyD88-dependent pathways in pDCs. Recognition of viral ssRNA and dsDNA via TLR7/8 and TLR9, respectively, triggers the recruitment of MyD88, which in turn interacts with IRAKs and TRAF6. TRAF6-mediated ubiquitination leads to the activation of TAK1 and ultimately to NF-kB and MAPK activation. IRF5 and IRF7 are also activated, via MyD88. IRAKI is required to phosphorylate IRF7. IRF7 is also ubiquitinated via K63-polyubiquintation. The activated form of IRF7 can translocate to the nucleus and activate the transcription of IFN-P and IFN-a genes. TRAF6 and IRAKI are also involved in the activation of IRF5, which is essential for inflammatory cytokine gene induction. IRF5 is activated by all TLRs which signal via MyD88

cytokines

Fig. 2 MyD88-dependent pathways in pDCs. Recognition of viral ssRNA and dsDNA via TLR7/8 and TLR9, respectively, triggers the recruitment of MyD88, which in turn interacts with IRAKs and TRAF6. TRAF6-mediated ubiquitination leads to the activation of TAK1 and ultimately to NF-kB and MAPK activation. IRF5 and IRF7 are also activated, via MyD88. IRAKI is required to phosphorylate IRF7. IRF7 is also ubiquitinated via K63-polyubiquintation. The activated form of IRF7 can translocate to the nucleus and activate the transcription of IFN-P and IFN-a genes. TRAF6 and IRAKI are also involved in the activation of IRF5, which is essential for inflammatory cytokine gene induction. IRF5 is activated by all TLRs which signal via MyD88

Several earlier studies had shown that IRF5 and IRF7 could regulate the expression of overlapping as well as distinct IFN-a subtypes (Barnes et al. 2002). In human cells, Schoenemeyer et al. demonstrated that ectopic expression of IRF5 enabled type I IFN production following TLR7 triggering and that knockdown of IRF5 by siRNA in human monocytes reduced this response. In contrast, Takaoka et al. showed that the induction of IFN-a in response to the TLR9

ligand, CpG-ODNs was normal in pDCs derived from IRF5-deficient mice. Observations from Mancl et al. identified nine distinct alternatively spliced IRF5 mRNAs (V1-V9) that have cell type-specific expression, localization, induc-ibility, and function in virus-mediated type I IFN gene induction (Mancl et al. 2005). Further investigations are needed to better understand the exact role of IRF5 in IFN induction in different pathways and in different cell types.

Consistent with a role for IRF5 in the regulation of inflammatory cytokine production, Schoenemeyer et al. showed that IRF5 is part of a complex with MyD88 and TRAF6 (Schoenemeyer et al. 2005), similarly to IRF7 (Kawai et al.

2004). This resemblance between MyD88-mediated activation of IRF7 and IRF5 is further enforced by the observation that IRAK-1 kinase is important in IRF5 activation (Schoenemeyer et al. 2005). IRF5 can also be phosphorylated and activated upon ectopic expression of TBK1 and IKKe (Cheng et al. 2006). The physiological relevance of these observations remains to be clarified, however, since inflammatory cytokine production (which is controlled by IRF5) is induced normally in TBK1 or IKKe knockout cells (Hemmi et al. 2004; N. Gout-agny and K.A. Fitzgerald, unpublished data). MyD88 also interacts with IRF4, which appears to negatively regulate the IRF5 signaling pathway (Negishi et al.

2005). IRF4 deficiency does not affect the ability of TLR7/9-stimulated pDCs to secrete IFN-a but caused overproduction of inflammatory cytokines. This was accompanied by enhanced activation of NF-kB and MAPKs. This hyperreactivity is observed not only in TLR7/9 but also in TLR2/4 signaling. IRF4, but not IRF7, can compete with IRF5 for association with MyD88, which can account for this phenotype of the IRF4 knockout mice. Our current understanding of the role of IRF5 in the antiviral immune responses is shown in Fig. 2.

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