IRF4

Last updated
IRF4
Protein IRF4 PDB 2dll.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IRF4 , LSIRF, MUM1, NF-EM5, SHEP8, interferon regulatory factor 4
External IDs OMIM: 601900; MGI: 1096873; HomoloGene: 1842; GeneCards: IRF4; OMA:IRF4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3662

16364

Ensembl

ENSG00000137265

ENSMUSG00000021356

UniProt

Q15306

Q64287

RefSeq (mRNA)

NM_001195286
NM_002460

NM_013674
NM_001347508

RefSeq (protein)

NP_001182215
NP_002451

NP_001334437
NP_038702

Location (UCSC) Chr 6: 0.39 – 0.41 Mb Chr 13: 30.93 – 30.95 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Interferon regulatory factor 4 (IRF4) also known as MUM1 is a protein that in humans is encoded by the IRF4 gene. [5] [6] [7] IRF4 functions as a key regulatory transcription factor in the development of human immune cells. [8] [9] The expression of IRF4 is essential for the differentiation of T lymphocytes and B lymphocytes as well as certain myeloid cells. [8] Dysregulation of the IRF4 gene can result in IRF4 functioning either as an oncogene or a tumor-suppressor, depending on the context of the modification. [8]

Contents

The MUM1 symbol is also the current HGNC official symbol for melanoma associated antigen (mutated) 1 (HGNC:29641).

Immune cell development

IRF4 is a transcription factor belonging to the Interferon Regulatory Factor (IRF) family of transcription factors. [8] [9] In contrast to some other IRF family members, IRF4 expression is not initiated by interferons; rather, IRF4 expression is promoted by a variety of bioactive stimuli, including antigen receptor engagement, lipopolysaccharide (LPS), IL-4, and CD40. [8] [9] IRF4 can function either as an activating or an inhibitory transcription factor depending on its transcription cofactors. [8] [9] IRF4 frequently cooperates with the cofactors B-cell lymphoma 6 protein (BCL6) and nuclear factor of activated T-cells (NFATs). [8] IRF4 expression is limited to cells of the immune system, in particular T cells, B cells, macrophages and dendritic cells. [8] [9]

T cell differentiation

IRF4 plays an important role in the regulation of T cell differentiation. In particular, IRF4 ensures the differentiation of CD4+ T helper cells into distinct subsets. [8] IRF4 is essential for the development of Th2 cells and Th17 cells. IRF4 regulates this differentiation via apoptosis and cytokine production, which can change depending on the stage of T cell development. [9] For example, IRF4 limits production of Th2-associated cytokines in naïve T cells while its upregulates the production of Th2 cytokines in effector and memory T cells. [8] While not essential, IRF4 is also believed to play a role in CD8+ cytotoxic T cell differentiation through its regulation of factors directly involved in this process, including BLIMP-1, BATF, T-bet, and RORγt. [8] IRF4 is necessary for effector function of T regulatory cells due to its role as a regulatory factor for BLIMP-1. [8]  

B cell differentiation

IRF4 is an essential regulatory component at various stages of B cell development. In early B cell development, IRF4 functions alongside IRF8 to induce the expression of the Ikaros and Aiolos transcription factors, which decrease expression of the pre-B-cell-receptor. [9] IRF4 then regulates the secondary rearrangement of κ and λ chains, making IRF4 essential for the continued development of the BCR. [8]

IRF4 also occupies an essential position in the adaptive immune response of mature B cells. When IRF4 is absent, mature B cells fail to form germinal centers (GCs) and proliferate excessively in both the spleen and lymph nodes. [9] IRF4 expression commences GC formation through its upregulation of transcription factors BCL6 and POU2AF1, which promote germinal center formation. [10] IRF4 expression decreases in B cells once the germinal center forms, since IRF4 expression is not necessary for sustained GC function; however, IRF4 expression increases significantly when B cells prepare to leave the germinal center to form plasma cells. [9]

Long-lived plasma cells

Long-lived plasma cells are memory B cells that secrete high-affinity antibodies and help preserve immunological memory to specific antigens. [11] IRF4 plays a significant role at multiple stages of long-lived plasma cell differentiation. The effects of IRF4 expression are heavily dependent on the quantity of IRF4 present. [10] A limited presence of IRF4 activates BCL6, which is essential for the formation of germinal centers, from which plasma cells differentiate. [11] In contrast, elevated expression of IRF4 represses BCL6 expression and upregulates BLIMP-1 and Zbtb20 expression. [11] This response, dependent on a high dose of IRF4, helps initiate the differentiation of germinal center B cells into plasma cells. [11]

IRF4 expression is necessary for isotype class switch recombination in germinal center B cells that will become plasma cells. B cells that lack IRF4 fail to undergo immunoglobulin class switching. [9] Without IRF4, B cells fail to upregulate the AID enzyme, a component necessary for inducing mutations in immunoglobulin switch regions of B cell DNA during somatic hypermutation. [9] In the absence of IRF4, B cells will not differentiate into Ig-secreting plasma cells. [9]

IRF4 expression continues to be necessary for long-lived plasma cells once differentiation has occurred. In the absence of IRF4, long-lived plasma cells disappear, suggesting that IRF4 plays a role in regulating molecules essential for the continued survival of these cells. [11]

Myeloid cell differentiation

Among myeloid cells, IRF4 expression has been identified in dendritic cells (DCs) and macrophages. [8] [9]

Dendritic cells (DCs)

The transcription factors IRF4 and IRF8 work in concert to achieve DC differentiation. [8] [9] IRF4 expression is responsible for inducing development of CD4+ DCs, while IRF8 expression is necessary for the development of CD8+ DCs. [9] Expression of either IRF4 or IRF8 can result in CD4-/CD8- DCs. [9] Differentiation of DC subtypes also depends on IRF4's interaction with the growth factor GM-CSF. [8] IRF4 expression is necessary for ensuring that monocyte-derived dendritic cells (Mo-DCs) can cross-present antigen to CD8+ cells. [8]

Macrophages

IRF4 and IRF8 are also significant transcription factors in the differentiation of common myeloid progenitors (CMPs) into macrophages. [8] IRF4 is expressed at a lower level than IRF8 in these progenitor cells; however, IRF4 expression appears to be particularly important for the development of M2 macrophages. [8] JMJD3, which regulates IRF4, has been identified as an important regulator of M2 macrophage polarization, suggesting that IRF4 may also take part in this regulatory process. [8]

Clinical significance

In melanocytic cells the IRF4 gene may be regulated by MITF. [12] IRF4 is a transcription factor that has been implicated in acute leukemia. [13] This gene is strongly associated with pigmentation: sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. [14] A variant has been implicated in greying of hair. [15]

The World Health Organization (2016) provisionally defined large B-cell lymphoma with IRF4 rearrangement as a rare indolent large B-cell lymphoma of children and adolescents. This indolent lymphoma mimics, and must be distinguished from, pediatric-type follicular lymphoma. [16] The hallmark of large B-cell lymphoma with IRF4 rearrangement is the overexpression of the IRF4 gene by the disease's malignant cells. This overexpression is forced by the acquisition in these cells of a translocation of IRF4 from its site on the short (i.e. p) arm of chromosome 6 at position 25.3 [17] to a site near the IGH@ immunoglobulin heavy locus on the long (i.e. q) arm of chromosome 14 at position 32.33 [18] [19]

Interactions

IRF4 has been shown to interact with:

See also

Related Research Articles

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

<span class="mw-page-title-main">Germinal center</span> Lymphatic tissue structure

Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, proliferate, differentiate, and mutate their antibody genes during a normal immune response; most of the germinal center B cells (BGC) are removed by tingible body macrophages. There are several key differences between naive B cells and GC B cells, including level of proliferative activity, size, metabolic activity and energy production. The B cells develop dynamically after the activation of follicular B cells by T-dependent antigen. The initiation of germinal center formation involves the interaction between B and T cells in the interfollicular area of the lymph node, CD40-CD40L ligation, NF-kB signaling and expression of IRF4 and BCL6.

<span class="mw-page-title-main">Interferon regulatory factors</span> Protein family

Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons. Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a structure that binds specifically to the IRF-element (IRF-E) motifs, which is located upstream of the interferon genes. Some viruses have evolved defense mechanisms that regulate and interfere with IRF functions to escape the host immune system. For instance, the remaining parts of the interferon regulatory factor sequence vary depending on the precise function of the protein. The Kaposi sarcoma herpesvirus, KSHV, is a cancer virus that encodes four different IRF-like genes; including vIRF1, which is a transforming oncoprotein that inhibits type 1 interferon activity. In addition, the expression of IRF genes is under epigenetic regulation by promoter DNA methylation.

<span class="mw-page-title-main">IRF3</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor.

<span class="mw-page-title-main">Corepressor</span> Molecule that represses the expression of genes

In genetics and molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, but instead indirectly regulates gene expression by binding to repressors.

<span class="mw-page-title-main">STAT6</span> Protein and coding gene in humans

Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor complex to the nucleus and activate gene expression. Similarly as other STAT family proteins, STAT6 is also activated by growth factors and cytokines. STAT6 is mainly activated by cytokines interleukin-4 and interleukin-13.

<span class="mw-page-title-main">STAT2</span> Protein-coding gene in Homo sapiens

Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). It functions as a transcription factor downstream of type I interferons. STAT2 sequence identity between mouse and human is only 68%.

<span class="mw-page-title-main">BCL6</span> Transcription factor for converting Naive T cells to TFH

Bcl-6 is a protein that in humans is encoded by the BCL6 gene. BCL6 is a master transcription factor for regulation of T follicular helper cells proliferation. BCL6 has three evolutionary conserved structural domains. The interaction of these domains with corepressors allows for germinal center development and leads to B cell proliferation.

<span class="mw-page-title-main">PD-L1</span> Mammalian protein found in humans

Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.

<span class="mw-page-title-main">IRF2</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 2 is a protein that in humans is encoded by the IRF2 gene.

<span class="mw-page-title-main">IRF7</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 7, also known as IRF7, is a member of the interferon regulatory factor family of transcription factors.

<span class="mw-page-title-main">IRF1</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 1 is a protein that in humans is encoded by the IRF1 gene.

<span class="mw-page-title-main">GPR183</span> Protein-coding gene in the species Homo sapiens

G-protein coupled receptor 183 also known as Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a protein (GPCR) expressed on the surface of some immune cells, namely B cells and T cells; in humans it is encoded by the GPR183 gene. Expression of EBI2 is one critical mediator of immune cell localization within lymph nodes, responsible in part for the coordination of B cell, T cell, and dendritic cell movement and interaction following antigen exposure. EBI2 is a receptor for oxysterols. The most potent activator is 7α,25-dihydroxycholesterol (7α,25-OHC), with other oxysterols exhibiting varying affinities for the receptor. Oxysterol gradients drive chemotaxis, attracting the EBI2-expressing cells to locations of high ligand concentration. The GPR183 gene was identified due to its upregulation during Epstein-Barr virus infection of the Burkitt's lymphoma cell line BL41, hence its name: EBI2.

<span class="mw-page-title-main">Interferon alpha-1</span> Protein-coding gene in the species Homo sapiens

Interferon alpha-1 is a protein that in humans is encoded by the IFNA1 gene.

<span class="mw-page-title-main">IRF5</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 5 is a protein that in humans is encoded by the IRF5 gene. The IRF family is a group of transcription factors that are involved in signaling for virus responses in mammals along with regulation of certain cellular functions.

<span class="mw-page-title-main">PRDM1</span> Protein-coding gene in the species Homo sapiens

PR domain zinc finger protein 1, or B lymphocyte-induced maturation protein-1 (BLIMP-1), is a protein in humans encoded by the gene PRDM1 located on chromosome 6q21. BLIMP-1 is considered a 'master regulator' of hematopoietic stem cells, and plays a critical role in the development of plasma B cells, T cells, dendritic cells (DCs), macrophages, and osteoclasts. Pattern Recognition Receptors (PRRs) can activate BLIMP-1, both as a direct target and through downstream activation. BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades. As a fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios. BLIMP-1 is highly expressed in exhausted T-cells – clones of dysfunctional T-cells with diminished functions due to chronic immune response against cancer, viral infections, or organ transplant.

<span class="mw-page-title-main">IRF8</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene. IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell.

<span class="mw-page-title-main">BCL11A</span> Protein-coding gene in the species Homo sapiens

B-cell lymphoma/leukemia 11A is a protein that in humans is encoded by the BCL11A gene.

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

Pediatric-type follicular lymphoma (PTFL) is a disease in which malignant B-cells accumulate in, overcrowd, and cause the expansion of the lymphoid follicles in, and thereby enlargement of the lymph nodes in the head and neck regions and, less commonly, groin and armpit regions. The disease accounts for 1.5% to 2% of all the lymphomas that occur in the pediatric age group.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000137265 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021356 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Grossman A, Mittrücker HW, Nicholl J, Suzuki A, Chung S, Antonio L, et al. (October 1996). "Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25". Genomics. 37 (2): 229–233. doi:10.1006/geno.1996.0547. PMID   8921401. S2CID   42646350.
  6. ↑ Xu D, Zhao L, Del Valle L, Miklossy J, Zhang L (July 2008). "Interferon regulatory factor 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes". Journal of Virology. 82 (13): 6251–6258. doi:10.1128/JVI.00163-08. PMC   2447047 . PMID   18417578.
  7. ↑ "Entrez Gene: IRF4 interferon regulatory factor 4".
  8. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Nam S, Lim J-S (2016). "Essential role of interferon regulatory factor 4 (IRF4) in immune cell development." Arch. Pharm. Res. 39: 1548–1555. doi:10.1007/s12272-016-0854-1.
  9. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Shaffer AL, Tolga Emre NC, Romesser PB, Staudt LM (2009). "IRF4: Immunity. Malignancy! Therapy?" Clinical Cancer Research. 15 (9): 2954-2961. doi:10.1158/1078-0432.CCR-08-1845
  10. 1 2 Laidlaw BJ, Cyster JG (2021). "Transcriptional regulation of memory B cell differentiation." Nat. Rev. Immunol. 21: 209–220. doi:10.1038/s41577-020-00446-2.
  11. 1 2 3 4 5 6 Khodadadi L, Cheng Q, Radbruch A and Hiepe F (2019). "The Maintenance of Memory Plasma Cells." Front. Immunol. 10: 721. doi:10.3389/fimmu.2019.00721.
  12. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, et al. (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–676. doi: 10.1111/j.1755-148X.2008.00505.x . PMID   19067971. S2CID   24698373.
  13. ↑ Adamaki M, Lambrou GI, Athanasiadou A, Tzanoudaki M, Vlahopoulos S, Moschovi M (2013). "Implication of IRF4 aberrant gene expression in the acute leukemias of childhood". PLOS ONE. 8 (8): e72326. Bibcode:2013PLoSO...872326A. doi: 10.1371/journal.pone.0072326 . PMC   3744475 . PMID   23977280.
  14. ↑ Praetorius C, Grill C, Stacey SN, Metcalf AM, Gorkin DU, Robinson KC, et al. (November 2013). "A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway". Cell. 155 (5): 1022–1033. doi:10.1016/j.cell.2013.10.022. PMC   3873608 . PMID   24267888.
  15. ↑ Adhikari K, Fontanil T, Cal S, Mendoza-Revilla J, Fuentes-Guajardo M, Chacón-Duque JC, et al. (March 2016). "A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features". Nature Communications. 7: 10815. Bibcode:2016NatCo...710815A. doi:10.1038/ncomms10815. PMC   4773514 . PMID   26926045.
  16. ↑ Lynch RC, Gratzinger D, Advani RH (July 2017). "Clinical Impact of the 2016 Update to the WHO Lymphoma Classification". Current Treatment Options in Oncology. 18 (7): 45. doi:10.1007/s11864-017-0483-z. PMID   28670664. S2CID   4415738.
  17. ↑ "IRF4 interferon regulatory factor 4 [Homo sapiens (Human)] - Gene - NCBI".
  18. ↑ "IGH immunoglobulin heavy locus [Homo sapiens (Human)] - Gene - NCBI".
  19. ↑ Woessmann W, Quintanilla-Martinez L (June 2019). "Rare mature B-cell lymphomas in children and adolescents". Hematological Oncology. 37 (Suppl 1): 53–61. doi: 10.1002/hon.2585 . PMID   31187530.
  20. 1 2 Gupta S, Jiang M, Anthony A, Pernis AB (December 1999). "Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4". The Journal of Experimental Medicine. 190 (12): 1837–1848. doi:10.1084/jem.190.12.1837. PMC   2195723 . PMID   10601358.
  21. ↑ Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH (April 2002). "Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression". The Journal of Experimental Medicine. 195 (8): 1003–1012. doi:10.1084/jem.20011128. PMC   2193700 . PMID   11956291.
  22. ↑ Brass AL, Zhu AQ, Singh H (February 1999). "Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers". The EMBO Journal. 18 (4): 977–991. doi:10.1093/emboj/18.4.977. PMC   1171190 . PMID   10022840.
  23. ↑ Escalante CR, Shen L, Escalante MC, Brass AL, Edwards TA, Singh H, Aggarwal AK (July 2002). "Crystallization and characterization of PU.1/IRF-4/DNA ternary complex". Journal of Structural Biology. 139 (1): 55–59. doi:10.1016/S1047-8477(02)00514-2. PMID   12372320.

Further reading

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