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The Molecular Choreography of IRF4 and IRF8 with Immune System Partners

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The Molecular Choreography of IRF4 and IRF8 with Immune System Partners The Molecular Choreography of IRF4 and IRF8 with Immune System Partners 1,2,4 1,3 1 HARINDER SINGH, ELKE GLASMACHER, ABRAHAM B. CHANG, 1 AND BRYAN VANDER LUGT 1Department of Discovery Immunology, Genentech Inc., South San Francisco, California 94080 4Correspondence: [email protected] The transcription factors IRF4 and IRF8 represent immune-specific members of the interferon regulatory family. They play major roles in controlling the development and functioning of innate and adaptive cells. Genes encoding these factors appear to have been coopted by the immune system via gene duplication and divergence of regulatory and protein coding sequences to enable the acquisition of unique molecular properties and functions. Unlike other members of the IRF family, IRF4 and IRF8 do not activate transcription of Type 1 interferon genes or positively regulate interferon-induced gene expression. Instead, they bind to unusual composite Ets-IRF or AP-1-IRF elements with specific Ets or AP-1 family transcription factors, respectively, and regulate the expression of diverse sets of immune response genes in innate as well as adaptive cells. The molecular cloning of interferon regulatory factor et al. 2012). Strikingly, this involves cooperative assembly 8 (IRF8) as interferon consensus sequence-binding pro- of IRF4 with AP-1 heterodimers containing a basic leucine tein (ICSBP) led to the realization that it bound inter- zipper transcription factor, AFT-like (BATF) subunit. feron response sequence elements (ISRE), albeit with This molecular property is shared by IRF8 but not by other low affinity, and antagonized ISRE-mediated gene acti- IRF family members, reminiscent of the molecular specif- vation (Driggers et al. 1990). A breakthrough came with icity of PU.1-IRF4 or PU.1-IRF8 complexes (Glasmacher the characterization of IRF4 (Pip/ICSAT/LSIRF), which et al. 2012). Thus, IRF4 and IRF8 proteins have evolved revealed not only its structural relatedness to IRF8 but also not only to interact with specific members of the Ets super- its unusual property of cooperatively assembling with the family, namely PU.1 and Spi-B, but also with particular Ets family factor PU.1 on Ets-IRF composite elements members of the AP-1 superfamily, namely, BATF-con- (EICEs) (Eisenbeis et al. 1995). IRF8 shared the same taining heterodimers. Intriguingly, these select members distinctive molecular property and this led to the concept of the Ets and AP-1 family also have their expression that key functions of IRF4 and IRF8 in B lineage and largely confined to cells of the immune system. Therefore, myeloid cells could be executed via complexes with considerable protein evolution within the IRF, Ets, and PU.1 assembled on EICE motifs. IRF4 and IRF8 function AP-1 families has enabled the establishment of unique equivalently in controlling pre-B-cell differentiation (Lu immune-specific partnerships. In this perspective, major et al. 2003). IRF4, on the other hand, uniquely regulates biological functions of IRF4 and IRF8 within the immune immunoglobulin gene class switch recombination (CSR) system are discussed in light of these two types of immune- in activated B cells and their differentiation into plasma specific transcription factor complexes. cells (Sciammas et al. 2006). Conversely, IRF8 has a dom- inant function in regulating the proliferation of myeloid progenitors and their differentiation into macrophages ROLES OF IRF4 AND IRF8 IN B-CELL (Tamura et al. 2000). DEVELOPMENT AND ACTIVATION The observations that IRF4 regulates differentiation of T cells into effector states such as Th2 and Th17 raised a IRF4 was cloned using a cDNA expression library and a molecularconundrum because the aforementioned T help- DNA probe that corresponded to an EICE present in an er cells express very low levels of the interaction partner immunoglobulin (Ig) l light-chain gene enhancer (Eisen- PU.1 or the related Ets factor Spi-B (Lohoff et al. 2002). beis et al. 1995). As anticipated by earlier biochemical These findings suggested the existence of a novel partner analysis, the recombinant protein was shown to coopera- for IRF4 and IRF8. ChIP-seq analysis of IRF4-targeted tively bind to EICE sequences present in Ig l as well as Ig sequences in T cells revealed that IRF4 binds to a novel k gene enhancers. Based on these biochemical properties, setof AP-1-IRF composite elements (AICE) (Ciofani et al. the protein was initially termed Pip for PU.1 interac- 2012; Glasmacher et al. 2012; Li et al. 2012; Tussiwand tion partner and later redesignated as IRF4 based on its 2Currentaddress:DivisionofImmunobiologyandtheCenterforSystemsImmunology,CincinnatiChildren’sHospitalMedicalCenter,Cincinnati,OH45229. 3Current address: Helmholtz Zentrum Mu¨nchen, 85764 Neuherberg, Germany Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/sqb.2013.78.020305 Cold Spring Harbor Symposia on Quantitative Biology, Volume LXXVIII 101 102 SINGH ET AL. relatedness to other IRF family members, particularly distinct sets of genes? ChIP-seq experiments with B cells IRF8. cDNA clones of IRF4 (LSIRF/ICSAT) were also activated in vitro have provided an important molecular isolated by two other laboratories based on its expression clue. During the initial stages of B-cell activation, IRF4 is in lymphocytes (Matsuyama et al. 1995; Yamagata et al. seen to bind predominantly to EICE motifs. At a later time 1996). The binding of IRF4, in a cooperative manner with point when plasma cells expressing higher levels of IRF4 the transcription factor PU.1, to functionally important are generated, there is increased occupancy of IRF4 at regulatory motifs in the Ig k 30 and l enhancers suggested ISRE motifs. These latter motifs represent interferon- an important role in the developmental activation of Ig stimulated response elements that are bound with low light-chain transcription and rearrangement. Analysis of affinity by IRF4 homodimers. Intriguingly, these IRF4- IRF4 knockout (KO) mice did not reveal a defect in B-cell bound ISRE motifs are enriched in genes that are prefer- development. However, the combined loss of IRF4 and entially expressed in plasma cells. These results have led IRF8 resulted in a profound block to B-cell development, to the proposal that plasma cell differentiation is depen- precisely at the cycling pre-B-cell stage (Lu et al. 2003). dent on sustained and higher levels of IRF4 expression The Irf42/2, Irf82/2 pre-B cells were impaired for the because this enables efficient occupancy of low-affinity activation of germline k and l gene transcription as well ISRE motifs that are associated with plasma cell genes. as DNA recombination. Thus, the genetic analysis satis- fied the molecular predictions and suggested that IRF4 and IRF8 were molecularly redundant in the context of DISCOVERY OF IRF4-BATF COMPLEXES pre-B cells. This was formally showed by complementing REGULATING HELPER-T-CELL Irf42/2, Irf82/2 pre-B cells with IRF4 or IRF8 (Ma et al. DIFFERENTIATION 2006). Although IRF4 is not required for B-cell development, IRF4 is important for the differentiation of various T- it regulates B-cell activation and has been shown to or- helper (Th)-cell subsets, including Th2, Th9, Th17, and chestrate Ig CSR as well as plasma cell differentiation Tfh cells (Glasmacher et al. 2012). The role for IRF8 in (Sciammas et al. 2006). Even though mature B cells ex- Th differentiation has not been as intensively investigat- press both IRF4 and IRF8, in this cellular context the two ed. Interestingly, IRF8 KO T cells more readily differ- transcription factors do not function in a molecularly re- entiate into Th17 cells, in contrast with their wild-type dundant or equivalent manner. IRF4 promotes CSR in counterparts (Ouyang et al. 2011). Thus, IRF8 appears to activated B cells and their differentiation into plasma cells antagonize the function of IRF4 in this cellular context. by positively regulating the expression of the Aicda and Until recently, the molecular mechanisms by which Blimp1 genes, respectively. Importantly, these genes are IRF4 and IRF8 might regulate gene expression in helper reflective of two mutually antagonistic programs of B-cell T cells had remained enigmatic. It had been suggested gene expression. IRF4 controls the transition between the that in Th2 cells, IRF4 could interact with nuclear factor competing programs of gene expression in a concentra- of activated T cells (NFAT) to regulate interleukin-4 ex- tion-dependent manner with low levels favoring CSR and pression (Rengarajan et al. 2002), whereas in T cells that higher levels inducing plasma cell differentiation. Based respond to IL-21, IRF4 was proposed to interact with on these findings, IRF4 was also proposed to regulate the STAT3 to regulate Blimp1 expression (Kwon et al. mutually antagonistic programs of gene expression that 2009). However, the generality of these interactions and are characteristic of germinal center B cells and plasma the biochemical mechanisms underlying DNA assembly cells. Furthermore, it was suggested to function as a key remained to be elucidated. As mentioned previously, component of a gene regulatory network that enables B IRF4 and IRF8, unlike other members of the IRF factor cells upon their activation to transiently acquire the GC family, bind with low affinity to ISREs but can be recruit- state before collapsing it and undergoing terminal differ- ed to high-affinity EICE motifs in B cells by interacting entiation into plasma cells. with the Ets family transcription factors, PU.1 and Spi-B. Recently, using both a constitutive and a conditional However, PU.1 and Spi-B are expressed at very low levels knockout of Irf4, it has been established that IRF4 is re- in T-helper-cell lineages, except in Th9 cells. Recently, quired for the generation of germinal center B cells four independent studies have described a novel molecu- (Ochiai et al. 2013). IRF4 controls the expression of the lar partnership by which IRF4 and IRF8 regulate gene Bcl6 and Obf1 genes, both of which are required for the expression in Th cells (Ciofani et al.
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