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. 2021 Aug 13;13(6):1219–1227. doi: 10.1007/s12551-021-00825-6

Molecular interactions of IRF4 in B cell development and malignancies

Srinivasan Sundararaj 1,✉, Marco G Casarotto 1,✉
PMCID: PMC8724474  PMID: 35059038

Abstract

Interferon regulatory factor 4 (IRF4) is a lymphoid transcription factor and a key regulator in the development of various immune cells, including T and B cells. It is well-known that IRF4 controls numerous decision-making processes relating to B cell development, including differentiation, maturation, and signalling. Consequently, genetic alterations that affect the functional aspects of IRF4 can result in clonal transformation and have been identified in various lymphoid malignancies. Over the last decades, a series of studies have demonstrated the critical cellular and structural basis underpinning IRF4-mediated B cell development and associated malignancies. In this review, we will briefly summarise the recent advances in understanding IRF4-mediated B cell development and related malignancies, with a particular focus on the molecular aspects that govern these processes.

Keywords: Interferon regulatory factor 4, B cell development, Molecular interactions, B cell malignancies

Introduction

Interferon regulatory factors (IRFs) are a family of transcription factors (TFs) that plays an essential role in various aspects of the innate and adaptive immune response, including immune cell development, differentiation, and regulation of the host immune response to pathogens and apoptosis (Taniguchi et al. 2001; Battistini 2009; Hiscott et al. 2003; Paun and Pitha 2007; Ozato et al. 2007). The IRF family comprises 9 members designated as IRF1-9 that are typically characterised by their recognition of promoters containing the IRF consensus sequence (GAAA) (Fujita et al. 1987). Of all the characterised IRFs, IRF4 (also known as pip, MUM1, LSIRF, NFEM5, and ICSAT) is considered unique due to its gene expression being restricted to immune cells, including B and T cells as well as dendritic cells. Furthermore, IRF4 is the only member of this family whose expression is not induced by interferons (IFNs) (Nam and Lim 2016) but is rather mediated by a range of diverse mitogenic stimuli, including lipopolysaccharide (LPS), antigen receptor engagement, IL-4, and CD40 signalling (Gupta et al. 1999; El Chartouni et al. 2010; Honma et al. 2005). The functional importance of IRF4 in B cell development was first demonstrated with irf4-deficient mice, which exhibited profound splenomegaly and lymphadenopathy due to loss of homeostasis which is accompanied by an expansion of both B and T lymphocytes (Mittrucker et al. 1997). This seminal study has since been broadened and refined, expanding our understanding of the role of IRF4-mediated transcriptional regulation of B and T cells. Currently, IRF4 is characterised as one of the key drivers of B cell development; it is expressed at various stages of B cell development and controls several decisions that affect B cell differentiation and functional outcome, including maturation, B cell receptor (BCR) signalling, and transformation (Shukla and Lu 2014).

Structurally, IRF4 comprises two domains, namely, a highly conserved N-terminal DNA binding domain (DBD) and a C-terminal IRF association domain (IAD) linked by a flexible linker (Remesh et al. 2015; Nam and Lim 2016) (Fig. 1A). The DBD is characterised by the presence of five conserved tryptophan residues and underpins target DNA recognition. IAD, on the other hand, is a protein-protein interaction domain that is critical for its interaction with other IRF members and with TFs from different families. Within the IAD region, the last 30 amino acid residues comprise an auto-inhibitory region (AR) which binds the DBD to regulate its interaction with the target DNA.

Fig. 1.

Fig. 1

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Overview of IRF4 structure. A Schematic representation of the IRF4 structure showing different domain architecture. B Cartoon representation of the crystal structure of IRF4 protein comprising DNA binding domain and IRF4 association domain linked by flexible linker. The secondary structural elements of DNA binding domain are coloured as α-helices, light blue; β-sheet, teal; and loops, red, respectively. IRF4 association domain secondary structural elements are coloured as α-helices, yellow; β-sheet, magenta; and loops, light blue, respectively

IRF4 can bind its target DNA as either a homodimer or as a heterodimer in conjunction with other TFs. Due to its versatile function, it is not surprising that numerous DNA targets have been identified to interact with IRF4. It binds the canonical IFN-Stimulated Response Elements (ISRE) as a homodimer and regulates the activation of IFN-stimulated genes (ISGs). Conversely, it engages Erythroblast Transformation Specific (Ets), IFN Composite Elements (EICE), and AP-1-IRF Composite Elements (AICE1 or 2) as a heterodimer and requires PU.1, SPIB, or BATF TFs for high-affinity interactions (Shukla et al. 2013). Traditionally, IRF4 was shown to bind weakly to its target DNA as a homodimer. This inherent weaker binding was attributed to the presence of the AR region, which by engaging with the DBD occluded its direct interaction with the DNA (Brass et al. 1999; Brass et al. 1996). Studies have shown that upon interaction with the binding partner, this auto-inhibition is relieved, allowing IRF4 to bind tightly to its target DNA sequence. In the case of the IRF4/PU.1/EICE interaction, the phosphorylation of serine 148, located in the PEST region of PU.1, mediates formation of the complex through its interaction with the residues located in the IAD region, mainly Arg-398 and Lys-399 (Brass et al. 1999). Likewise, recognition of the AICE motif requires cooperative interaction with the BATF and JUN heterodimer, wherein His-55, Glu-77, and Lys-63 of BATF coordinate the high-affinity interaction (Glasmacher et al. 2012; Tussiwand et al. 2012). It remains unknown how this autoinhibition is relieved during formation of the homodimeric IRF4 complex. Nevertheless, high local concentration of IRF4 was presumed to play a role in IRF4 homodimerization (Ochiai et al. 2013). Notably, the choice of heterodimeric complex formation depends largely on the target cell type and is essential for the cellular outcome. The binding of IRF4 with Ets TFs is largely restricted to B cells and dendritic cells (Brass et al. 1999), whereas the heterodimeric complex formed between IRF4 and AP-1 TFs is the main complex in T cells but is also relevant during germinal center (GC) B cell and plasma cell (PC) regulation (Ochiai et al. 2013).

IRF4 in B cell development

IRF4 plays an essential role in the development of B cells. Together with IRF8, it is known to regulate pre-B cell development. Remarkably, studies have shown that pre-B cell development is completely blocked in IRF4,8−/−deficient mice (Lu et al. 2003), highlighting their critical role in the early development of B cells. It was demonstrated that IRF4 and IRF8 facilitate the transition from pre-B cells by inducing the expression of Ikaros family TFs (Ma et al. 2008). Moreover, the development of germinal center (GC) B cells and plasma cells (PC) depends largely on the regulation of IRF4. Evidence demonstrating a dynamic change in IRF4 levels during germinal center reaction led to the proposal of a kinetic model to explain how various changes in GCs are regulated by the distinct expression of IRF4 (Cattoretti et al. 2006; Ochiai et al. 2013; Sciammas et al. 2011). Accordingly, it is proposed that IRF4 regulates these processes in a temporal and concentration-dependent manner. At low concentration, IRF4 binds EICE1 and AICE DNA motifs as a heterodimer in conjunction with PU.1 or BATF and upregulates activation-induced cytidine deaminase (AID), an enzyme that is critical for processes such as class-switch recombination (CSR) and somatic hypermutation (SHM) (Muramatsu et al. 2000). In addition, it activates B cell lymphoma 6 protein (BCL6), a transcriptional repressor required for GC B cell formation and antibody affinity maturation (Willis et al. 2014). Knockdown of IRF4 leads to a marked reduction in the induction of both AID and BCL6 and therefore the development of GC cells and related processes, thereby highlighting the key role played by IRF4 in GC formation. Conversely, at higher concentration, IRF4 engages the ISRE motif as a homodimer and regulates the expression of the Blimp-1 TF, an essential modulator of the plasma cell differentiation programme (Shaffer et al. 2002). Notably, it has been shown that in the absence of IRF4, Blimp-1 expression is not sufficient for PC differentiation (Tellier et al. 2016), thus indicating the pivotal role of IRF4 in PC differentiation. Additionally, IRF4 is known to contribute crucially to other developmental aspects, including CSR, a process where the constant region of immunoglobulin heavy chain (IgH) undergoes rearrangement to yield antibodies with different effector functions, and SHM, a process by which the variable region of the immunoglobulin is altered to select high-affinity antibodies producing B cells.

Structural features of IRF4

The crystal structures of the IRF4 DBD in both bound and unbound forms have been determined and shown to have comparable structural features to other IRF members (Escalante et al. 1998; Furui et al. 1998). Specifically, IRF4 DBD exhibits an α/β structural architecture comprising three α-helices (α1–α3) flanked by four anti-parallel β-sheets (β1–β4) which together form the helix-turn-helix motif observed commonly in other TFs, such as catabolite gene activator protein (CAP)-related proteins and hepatocyte nuclear factor 3γ (HNF-3γ) (Clark et al. 1993; Schultz et al. 1991). However, it differs markedly by the presence of three unusually lengthy connecting loops, designated as loop 1 to loop 3. These loops are responsible for connecting the different parts of the secondary structural elements. For example, loop 1 and loop 2 connect β2 and α2 and α2 and α3 helix (recognition helix), respectively, whereas loop 3 forms the connection for β3 and β4 (Fig. 1B).

Similarly, the crystal structure of IRF4 IAD lacking the AR region has also been determined (Remesh et al. 2015). The structure adopts an MH2 fold typical to the SMAD family of proteins. Notably, this structural feature resembles the structure of two other IRF members, IRF3 and IRF5 (Chen et al. 2008; Qin et al. 2003). Similar to the DBD structure, the IAD structure adopts α/β structural topology, albeit predominated by β-sheets. Namely, it comprises four α-helices (α1–α4) and as many as eleven β-barrels (β1–β11) and five lengthy connecting loops which, as like the DBD, connects the various parts of the secondary structure (Fig. 1B). Collectively, these structural features lead IAD to adopt a sickle-like shape (Remesh et al. 2015). Comparison of the IRF4 IAD with the IRF3 and IRF5 IADs has provided some insights into key unique structural features, in particular for loop 3 and loop 5 which exhibited different conformations (Remesh et al. 2015).

While the overall crystal structure of the full-length IRF4 protein is yet to be determined, the low-resolution SAX structure has been obtained. The structure revealed that the linker which connects DBD and IAD adopts a folded conformation and may interact directly with these domains. Moreover, it also showed that the AR region is flexible without docking onto the IAD, as observed in the IRF3 structure (Remesh et al. 2015).

Structural overview of the IRF4/DNA complex

The crystal structures of the IRF4/DNA complexes in both homodimeric and heterodimeric forms in conjunction with PU.1 TF have been determined (Escalante et al. 2002; Sundararaj et al. 2021). The overall structure has revealed that IRF4 binds the target DNA in a head-to-tail orientation with the insertion of an a3-recognition helix directly on the GAAA sequence, a feature reminiscent of IRF/DNA complex structures (Escalante et al. 1998; Panne et al. 2004; Fujii et al. 1999; Escalante et al. 2007), suggesting that IRF, in general, adopts a highly conserved recognition mode to engage the target DNA (Fig. 2). Most notably, in both cases, docking of IRF4 onto the target DNA has a considerable impact on the DNA structure. Specifically, we and others have shown that engagement of IRF4, either as a homodimer or heterodimer, distorts its structure leading to a substantial bending ranging from 15 to 21°, thereby inducing an unusual S-shaped topology (Escalante et al. 2002, Sundararaj et al. 2021). This distortion of DNA was critical for enabling the IRF4 and its cognate TF, PU.1 in the case of IRF4/PU.1/DNA heterodimeric complex, to optimally engage the target DNA (Escalante et al. 2002, Sundararaj et al. 2021). Further, the overall structures also revealed that the connecting loop, especially loop L1, interacts directly with the DNA backbone, thereby contributing to an extensive DNA interaction footprint.

Fig. 2.

Fig. 2

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Cartoon representation of the IRF4/DNA complex structures. A IRF4/DNA homodimer complex. B IRF4/PU.1/DNA heterodimer complex. IRF4, magenta; α3-recognition helix of IRF4, yellow; DNA, orange; PU.1, deep teal; recognition helix of PU.1, green

Structural differences between homodimer and heterodimer complexes

Our recent determination of the crystal structure of the IRF4/DNA homodimer has enabled molecular insights into the stereochemical differences between the IRF4 homodimer and heterodimer complexes. One of the most striking features lies in the manner in which the recognition helices engage the target DNA. In the case of the IRF4/PU.1/DNA heterodimer complex, the recognition helix of the PU.1 adopts a perpendicular orientation to the sugar-phosphate backbone of the DNA axis, whereas the interacting IRF4 monomer lies almost in a parallel orientation (Fig. 3A). This parallel-perpendicular orientation in the recognition helix results in the connecting loop L2 of PU.1 draping over the DNA to make a protein-protein-mediated intermolecular interaction with the IRF4 DBD. Specifically, the inward positioning of L2 causes Arg 222 and Lys 223 of PU.1 to extend across the minor groove to engage with Asp 117 of IRF4 through electrostatic interactions (Fig. 3B). Binding is further enhanced by van der Waal-mediated contacts spanning Arg 222 of PU.1 and Leu116 and Val111 of IRF4 and by a water-mediated hydrogen-bonding network that connects Lys 219 of PU.1 to His 56 of IRF4 (Escalante et al. 2002). Thus, in the case of the heterodimer complex, the co-ordinated protein-protein and protein-DNA interactions underpin the observed higher affinity interaction of the complex. Conversely, the homodimer structure has shown that the recognition helix of both the interacting IRF4 monomers takes up a parallel orientation to the sugar-phosphate backbone of the DNA axis. This in turn causes their connecting loops L2 to move away from each other, thereby preventing any possible protein-protein contact between the interacting IRF4 domains (Fig. 3C). As such, formation of the homodimer complex is completely dependent on the protein-DNA contact (Sundararaj et al. 2021), thus providing a possible rationale for the inherently weaker affinity observed for the ISRE DNA (Bovolenta et al. 1994). The other key differences lie in the change in the orientation of the connecting loop L1, which enables a highly conserved Arg 59 in the homodimer complex to interact directly with the consensus sequence, a feature not observed in the heterodimer complex.

Fig. 3.

Fig. 3

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Stereochemical differences in IRF4/DNA complexes. A Surface representation of the IRF4/PU.1/DNA heterodimer complex. B Cartoon representation of the protein-protein in the IRF4 heterodimer complex. C Surface representation of the IRF4/DNA homodimer complex. IRF4, magenta; PU.1, deep teal; DNA, orange; α3-recognition helix of IRF4, yellow; recognition helix of PU.1, green; interacting residues, black; electrostatic interaction, black dashed line

IRF4 in B cell malignancies

Due to its critical role in the development of B and T cells, IRF4 dysfunction has been implicated in numerous lymphoid malignancies. Intriguingly, in almost all the cases, the mutation is detected in the DNA binding domain, implying that the IRF4/DNA interaction is a key driver for malignant transformation (Table 1) (Bruno et al. 2014). Chronic lymphocytic leukaemia (CLL), a mature B cell-derived neoplasia, is characterised by the outgrowth of CD19/CD5 double-positive B cells, accounting for 25–30% of all leukaemias in the western world (Asslaber et al. 2019). Several studies have demonstrated the possible involvement of IRF4 in the CLL development and broadly recognised IRF4 as a tumour suppressor in CLL. Genome-wide analysis of CLL patients has identified IRF4 as a strong candidate for susceptibility to CLL (Di Bernardo et al. 2008). Moreover, fine-scale mapping of the 6p25.3 susceptibility locus has mapped the 3-untranslated region of IRF4 in CLL susceptibility (Crowther-Swanepoel et al. 2010). Furthermore, in Tcl-1 transgenic mice, IRF4 deletion was shown to accelerate CLL development with an enhanced tumour immune evasion (Asslaber et al. 2019). In addition, a recurrent somatic heterozygous mutation affecting the IRF4 DBD (IRF4 L116R) was identified in 1.5% of CLL patients. More recently, the direct role of IRF4 in the modulation of B cell receptor (BCR) signalling in CLL cells has been established (Maffei et al. 2021).

Table 1.

Overview of IRF4 lymphoid malignancies. The table was prepared on the basis of the deposited mutations in COSMIC cancer database (mutations with a count of less than 4 in the database are excluded)

IRF4 location Mutation Lymphoid malignancies References
DNA binding domain K59R Adult T cell lymphoma-leukaemia (Kataoka et al. 2015)
DNA binding domain L70V

Adult T cell lymphoma-leukaemia

Diffuse large B cell lymphoma

 (Kataoka et al. 2015, Lacy et al. 2020)
DNA binding domain C99R Diffuse large B cell lymphoma (Zehir et al. 2017)
DNA binding domain S114R Adult T cell lymphoma-leukaemia (Kataoka et al. 2015)
DNA binding domain K123R Multiple myeloma (White et al. 2018)
DNA binding domain G58D Diffuse large B cell lymphoma (Lacy et al. 2020)
DNA binding domain Q60K Diffuse large B cell lymphoma (Morin et al. 2011, Lacy et al. 2020)
DNA binding domain G58S

Primary central nervous system lymphoma

Diffuse large B cell lymphoma

 (Lacy et al. 2020, Bruno et al. 2014)
DNA binding domain S114N Adult T cell lymphoma-leukaemia (Kataoka et al. 2015)
IRF association domain P293S Marginal zone lymphoma (Rossi et al. 2012)
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IRF4 has also been identified as a key player in the development of multiple myeloma (MM), a neoplasia originating from the plasma cells (Agnarelli et al. 2018). Inhibition of IRF4 by RNA interference-based genetic screens has shown that it is toxic to all MM cell lines, regardless of their transforming oncogenic mechanism (Shaffer et al. 2008). In MM patients, IRF4 is overexpressed, consistent with their role as an oncogene and upregulates over 100 genes that are quiescent in the healthy PCs. Some of these genes include Stag2, CDK6, and MYC which are directly involved in the cell growth and survival (Shaffer et al. 2008). IRF4 also downregulates genes involved in the proapoptotic process in particular BMF and BIM belonging to the BH3-only subgroup of the BCL2 protein family, thereby extending the survival of MM cell lines (Fedele et al. 2020). The oncogenic nature of the IRF4 is often attributed to the genetic translocation and/or recurrent point mutations. Chromosomal translocation that juxtaposes the immunoglobulin heavy chain (IgH) locus to IRF4 results in concomitant overexpression of IRF4, which is often found in MM cases (Yoshida et al. 1999). Likewise, a recurrent somatic mutation (L116R, K123R) identified in the IRF4 DBD is often seen in MM patients (Chapman et al. 2011; Lohr et al. 2014).

The role of IRF4 has also been demonstrated in diffuse large B cell lymphoma (DLBCL). It represents a diverse group of B cell malignancies which are broadly divided into GC B cell type DLBCL (GCB type) and activated B cell type DLBCL (ABC type) subgroups (Alizadeh et al. 2000). IRF4 exhibits a distinct expression pattern in these subgroups; in that, it is highly expressed in the ABC type and shows negative expression in the GCB type (Cattoretti et al. 2006; Shukla and Lu 2014). IRF4 is known to downregulate BCL which is a characterised oncogene in DLBCL (Saito et al. 2007). Interestingly, subsets of DLBCL display mutations or chromosomal translocations that disrupt the IRF4 binding region in the BCL6 promoter (Saito et al. 2007). Cooperative interaction between IRF4 and ETS family member SPIB has been identified to promote malignant phenotype in ABC DLBCL (Yang et al. 2012). Strikingly, the drug lenalidomide was shown to reduce the burden of ABC DLBCL by downregulating IRF4 and SPIB (Yang et al. 2012). Furthermore, the ABC DLBCL malignancy is also promoted through the dysregulation of IRF4 known target Blimp-1. In ABC DLBCL, genetic alterations were observed PRDM1 (encoding Blimp-1) (Pasqualucci et al. 2006; Tam et al. 2006) thereby rendering it insensitive to IRF4 action.

Concluding remarks

Over the years, the role of IRF4 in B cell development has been well characterised, resulting in the identification of IRF4 as a key regulator for these processes. Not surprisingly, due to its intimate functional role in the B cell developmental pathway, genetic aberrations in IRF4 have been linked directly to numerous B cell malignancies. The crystal structures of IRF4 homodimer and heterodimer in combination with PU.1 TF have shed a light on the molecular details governing the IRF4’s role in B cell development. These structures have also provided an insight into the stereochemical differences between homo and heterodimer complex and their implication in the cooperative binding, thus providing an attractive opportunity for the development of IRF4-centered therapies. However, there are gaps in our understanding of IRF4 structures that limits the opportunities for novel therapies. For example, our current understanding of the homo/heterodimer complex formation stems from the crystal structures comprising just the DBDs. As such, the influence of IAD in the complex formation remains unknown. Moreover, the structural basis for the IRF4 autoinhibition remains to be determined. Interestingly, despite its essential functional role, there are no current drugs available in the market that explicitly targets IRF4, although studies are currently developing novel strategies to target IRF4. One such initiative involves the use of IRF4 anti-sense oligonucleotide (ASOs) which is showing promising signs as a viable option for the development of next-generation novel IRF4 therapies (Mondala et al. 2021; Rauch et al. 2020). Given the recent advances relating to IRF4 structures, we expect increased opportunities for the development of other novel strategies specifically targeting IRF4, leading to the development of precision IRF4-centered drugs and therapies.

Acknowledgements

The authors would like to thank Dr. Emmalene Bartlett (JCSMR, Australian National University) for critically proofreading the manuscript.

Declarations

Conflict of interest

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Srinivasan Sundararaj, Email: srinivasasn.sundararaj@anu.edu.au.

Marco G. Casarotto, Email: marco.casarotto@anu.edu.au

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