IRF4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0002376 immune system process	IBA GO_REF:0000033	ACCEPT	Summary: IRF4 is a lymphoid-restricted transcription factor that plays critical roles across multiple arms of the immune system, including B cell differentiation to plasma cells, T helper cell lineage commitment (Th2, Th9, Th17), effector CD8+ T cell differentiation, and dendritic cell and macrophage programs (PMID:12374808, deep research review). Reason: This broad IBA annotation is accurate. IRF4 is expressed almost exclusively in immune cells and its functions are overwhelmingly immunological. The IBA is supported by phylogenetic inference across the IRF family and is consistent with extensive experimental evidence for IRF4 roles in both adaptive and innate immunity. Supporting Evidence: PMID:12374808 Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4(+) T cells to produce cytokines.
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: IRF4 is a transcription factor that functions in the nucleus, where it binds DNA at ISRE, EICE, and AICE composite elements to regulate target gene transcription. Nuclear localization is confirmed by UniProt annotation (ECO:0000269\|PubMed:36917008) and structural studies of the DBD. Reason: Nuclear localization is a core feature of IRF4 function as a DNA-binding transcription factor. The IBA annotation is consistent with multiple experimental lines of evidence including immunofluorescence and functional characterization of disease-causing variants that alter nuclear partitioning. Supporting Evidence: PMID:36917008 Here, based on our investigation of a multigeneration family, we describe a novel autosomal dominant PAD caused by a pathogenic IRF4 variant affecting the IAD. All three patients in the family presented with low IgM, IgG, and IgA serum levels (diagnosed during childhood); low plasma cell counts; abnormal T cell subsets; and early hair graying.
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: IRF4 is a DNA-binding transcription factor that regulates RNA polymerase II transcription of target genes including cytokines (IL-2, IL-4, IL-10, IL-13, IL-17), immunoglobulin genes, and genes involved in lymphocyte differentiation programs. It transactivates luciferase reporters driven by IL-2 and IL-4 promoters (PMID:12374808). Reason: Regulation of Pol II transcription is the core biological process in which IRF4 participates. The IBA annotation is well-supported by the phylogeny of the IRF family and extensive experimental data from reporter assays, ChIP-seq, and genetic studies. Supporting Evidence: PMID:12374808 Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	IBA GO_REF:0000033	ACCEPT	Summary: IRF4 is a sequence-specific DNA-binding transcription factor that regulates RNA polymerase II-dependent transcription. It binds ISRE motifs and composite elements (EICE, AICE) with partner TFs to activate target gene transcription. This is supported by crystal structures of the DBD bound to DNA, reporter assays, and ChIP-seq data. Reason: This is the core molecular function of IRF4. The IBA annotation is consistent with extensive experimental evidence showing IRF4 functions as a DNA-binding transcription factor. Per GO-CAM TF annotation guidelines, this is the appropriate parent term for transcription factor activity. Supporting Evidence: PMID:12374808 Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: IRF4 binds sequence-specifically to cis-regulatory regions of Pol II-transcribed target genes, including ISRE motifs in MHC class I promoter, the immunoglobulin lambda light chain enhancer (with PU.1), and promoter regions of cytokine genes (IL-2, IL-4). The IRF4 DBD recognizes GAAA core motifs. Reason: This accurately captures IRF4's DNA-binding specificity at cis-regulatory regions. The IBA annotation is supported by direct evidence from EMSA, reporter assays, and ChIP-seq studies. IRF4 binds cis-regulatory elements in a sequence-specific manner, recognizing ISRE, EICE, and AICE motifs. Supporting Evidence: PMID:12374808 A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1.
GO:0000976 transcription cis-regulatory region binding	IEA GO_REF:0000002	ACCEPT	Summary: Electronic annotation based on InterPro domain IPR001346 (IRF DNA-binding domain). IRF4 does bind cis-regulatory regions through its conserved tryptophan pentad repeat DBD. Reason: This IEA annotation is accurate but less specific than the IBA annotation for GO:0000978. The InterPro-based mapping correctly identifies cis-regulatory region binding as a function of the IRF DNA-binding domain. It is acceptable as a broader parent of the more specific IBA terms.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine learning annotation for Pol II cis-regulatory region binding. Consistent with both the IBA annotation and direct experimental evidence. Reason: This IEA annotation is a duplicate of the IBA annotation at GO:0000978 and is correct. The ARBA-based electronic annotation independently supports the same molecular function.
GO:0003677 DNA binding	IEA GO_REF:0000043	MODIFY	Summary: General DNA binding annotation from UniProt keyword mapping. IRF4 does bind DNA through its N-terminal tryptophan pentad repeat domain (aa 21-129). Reason: While IRF4 unquestionably binds DNA, this term is too general and uninformative. More specific terms such as GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA binding) or GO:1990837 (sequence-specific double-stranded DNA binding) better capture IRF4's function. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding
GO:0003700 DNA-binding transcription factor activity	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation for DNA-binding transcription factor activity. Consistent with experimental evidence and more specific IBA/IDA annotations. Reason: This is a correct annotation. While the more specific child term GO:0000981 (RNA polymerase II-specific) is also annotated, this broader parent term from automated methods is not wrong and is acceptable as a general descriptor.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation for nuclear localization based on UniProt subcellular location vocabulary. Consistent with IRF4 being a nuclear transcription factor. Reason: Correct annotation. IRF4 is primarily nuclear, consistent with its function as a DNA-binding transcription factor. This is supported by both IBA and IMP annotations at the same term.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation for cytoplasmic localization based on UniProt subcellular location. UniProt reports cytoplasmic localization based on PMID:36917008. Reason: IRF4 is found in both nucleus and cytoplasm. The cytoplasmic pool likely represents either newly synthesized protein prior to nuclear import or a regulated cytoplasmic retention mechanism. This is consistent with the IMP annotation at the same term from PMID:36917008.
GO:0006355 regulation of DNA-templated transcription	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based annotation for regulation of DNA-templated transcription, based on IRF domains IPR019471 and IPR019817. Reason: This is a correct but general annotation. IRF4 is a transcription factor and regulation of DNA-templated transcription is its core biological process. While more specific terms exist (e.g., GO:0006357 regulation of transcription by RNA polymerase II), this broader IEA annotation from InterPro mapping is not wrong.
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine learning annotation for positive regulation of Pol II transcription. IRF4 primarily acts as a transcriptional activator. Reason: This is correct and consistent with the IDA annotation at the same term (PMID:12374808). IRF4 functions predominantly as a transcriptional activator, demonstrated by reporter assays showing transactivation of IL-2 and IL-4 promoter constructs.
GO:0051240 positive regulation of multicellular organismal process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA-based annotation for positive regulation of multicellular organismal process. Reason: This term is extremely broad and uninformative. While IRF4 does participate in processes that positively regulate multicellular organismal processes (e.g., immune cell differentiation), this annotation is too vague to be useful. More specific terms like regulation of T-helper cell differentiation or plasma cell differentiation are far more informative.
GO:0005515 protein binding	IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ...	MARK AS OVER ANNOTATED	Summary: This annotation derives from a large-scale innate immunity interactome study (HI5) that mapped protein interactions regulating type I interferon production. IRF4 (as bait or prey) was found to interact with IKBKAP (ELP1), IRAK1, TLK2, and YTHDC2 by affinity purification-mass spectrometry (PMID:21903422). The paper notes IKBKAP interacts with IRF4 and negatively regulates HSV-induced IFN production. Reason: While the physical interactions detected in this high-throughput screen are plausible, generic "protein binding" is uninformative. Some of these interactions (e.g., with ELP1/IKBKAP) are from a large-scale screen and may not reflect core IRF4 biology. The functionally important interactions of IRF4 are with PU.1/SPI1, BATF/JUN, SPIB, and DEF6, which are better described by more specific binding terms. Supporting Evidence: PMID:21903422 IKBKAP interacts with IRF4 and negatively regulates HSV-induced IFN production.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This annotation derives from the HuRI (Human Reference Interactome) project, a systematic binary interactome mapping using yeast two-hybrid. IRF4 interactions with GIPC2 and TSEN54 were detected. Reason: Generic "protein binding" from a high-throughput yeast two-hybrid screen is uninformative. The detected interactions (GIPC2, TSEN54) do not have clear functional relevance to IRF4's known biology as a transcription factor in immune cells. These may represent technical artifacts or biologically minor interactions. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies.
GO:0000786 nucleosome	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara-transferred annotation from mouse IRF4 (Q64287) suggesting IRF4 is part of nucleosomes. Reason: While IRF4 binds chromatin and may interact with nucleosomal DNA in the context of chromatin remodeling, being annotated as "part_of nucleosome" is misleading. IRF4 is not a histone or structural component of the nucleosome. It is a transcription factor that binds to cis-regulatory elements, some of which may be nucleosomal. The chromatin (GO:0000785) annotation is more appropriate.
GO:0000987 cis-regulatory region sequence-specific DNA binding	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara-transferred annotation from mouse IRF4 for cis-regulatory region sequence-specific DNA binding. Reason: This is correct and consistent with other annotations. IRF4 binds cis-regulatory regions in a sequence-specific manner at ISRE, EICE, and AICE motifs. This is a parent term of GO:0000978 which is also annotated.
GO:0003713 transcription coactivator activity	IEA GO_REF:0000107	MODIFY	Summary: Ensembl Compara-transferred annotation suggesting IRF4 has transcription coactivator activity, based on mouse ortholog data. Reason: IRF4 is primarily a DNA-binding transcription factor, not a coactivator. A coactivator does not directly bind DNA but enhances transcription through interaction with DNA-binding TFs. IRF4 directly binds DNA at ISRE/EICE/AICE elements. The appropriate term is GO:0001228 (DNA-binding transcription activator activity, RNA polymerase II-specific), which is already annotated with experimental evidence. This annotation likely derives from mouse studies where IRF4 cooperates with other TFs, but cooperation does not make it a coactivator. Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific
GO:0042832 defense response to protozoan	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara-transferred annotation from mouse IRF4 for defense response to protozoan. Mouse Irf4 is required for immune defense against Leishmania and Toxoplasma. Reason: While IRF4 is required for effective immune responses including those against protozoan parasites (primarily through its role in T cell differentiation and cytokine regulation), defense response to protozoan is not a core function of IRF4. It is a downstream consequence of IRF4's role in immune cell differentiation. The annotation is based on mouse ortholog data where IRF4 knockout mice show susceptibility to protozoan infection.
GO:0043565 sequence-specific DNA binding	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara-transferred annotation for sequence-specific DNA binding from mouse IRF4. Reason: This is correct. IRF4 binds DNA in a sequence-specific manner through its tryptophan pentad repeat DBD, recognizing GAAA core motifs. This is a parent term of the more specific cis-regulatory region binding terms also annotated.
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl Compara-transferred annotation for positive regulation of DNA-templated transcription. Reason: Correct and consistent with the IDA annotation at the same term from PMID:12374808. IRF4 functions primarily as a transcriptional activator, as demonstrated by reporter assays with IL-2 and IL-4 promoter constructs.
GO:0072540 T-helper 17 cell lineage commitment	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara-transferred annotation from mouse IRF4 for Th17 cell lineage commitment. Mouse studies show IRF4 is required for Th17 differentiation, binding and promoting Il17a/f, Il21, and Rorc expression. Reason: IRF4 is indeed essential for Th17 differentiation in mouse, and this role is conserved in human. However, Th17 lineage commitment is one of several immune cell differentiation programs regulated by IRF4 (also Th2, Th9, effector CD8+, plasma cells). This is a legitimate but non-core annotation representing one specific downstream function. The annotation is based on transfer from well-established mouse experimental data.
GO:0120162 positive regulation of cold-induced thermogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl Compara-transferred annotation from mouse IRF4 for positive regulation of cold-induced thermogenesis. This derives from a mouse study (PMID:24995979) showing IRF4 promotes thermogenic gene expression in brown adipose tissue. Reason: This annotation reflects a non-immune role of IRF4 in thermogenesis/adipose biology. While interesting, this is clearly a non-core function given that IRF4 is predominantly expressed in and functionally characterized in lymphoid cells. The human relevance of this mouse finding is uncertain.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on immunofluorescence data curated by the Human Protein Atlas (HPA). IRF4 is detected in the nucleoplasm by immunofluorescence in relevant cell types. Reason: Nucleoplasm localization is expected and correct for a transcription factor. The IDA evidence from immunofluorescence is reliable for localization. IRF4 functions in the nucleoplasm where it binds DNA and regulates transcription.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IMP PMID:36662884 A multimorphic mutation in IRF4 causes human autosomal domin...	ACCEPT	Summary: IMP annotation based on Fornes et al. (2023) Sci Immunol, which characterized IRF4 T95R variant in IMD131 patients. The T95R mutant gains neomorphic DNA binding to GATA-containing sequences not recognized by wildtype, while showing decreased transcription activation from canonical ISRE reporter constructs. This demonstrates that wildtype IRF4 normally has DNA-binding transcription activator activity. Reason: The mutant phenotype analysis confirms that wildtype IRF4 functions as a DNA-binding transcription activator. Loss of this activity in disease-causing variants directly supports the annotation. This is the most specific appropriate MF term per GO-CAM TF guidelines. Supporting Evidence: PMID:36662884 Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IMP PMID:36917008 A neomorphic mutation in the interferon activation domain of...	ACCEPT	Summary: IMP annotation based on Thouenon et al. (2023) J Exp Med, characterizing the IRF4 F359L neomorphic variant in IMD131 patients. The F359L variant shows loss of DNA-binding transcription activator activity, confirming this is the normal function of wildtype IRF4. Reason: Another disease variant study that confirms IRF4's transcriptional activator function through loss-of-function analysis. The F359L mutation in the IAD abolishes activator activity. Supporting Evidence: PMID:36917008 The mutant IRF4 failed to efficiently regulate the transcriptional activity of interferon-stimulated response elements (ISREs). Rapid immunoprecipitation mass spectrometry of endogenous proteins indicated that the mutant and wildtype IRF4 proteins differed with regard to their respective sets of binding partners.
GO:0005634 nucleus	IMP PMID:36917008 A neomorphic mutation in the interferon activation domain of...	ACCEPT	Summary: IMP annotation for nuclear localization from the Thouenon et al. (2023) study. The F359L variant shows no effect on subcellular location, indicating that wildtype (and mutant) IRF4 localizes to the nucleus. Reason: Nuclear localization is well-established for IRF4 and confirmed by this IMP study. This is expected for a DNA-binding transcription factor. Supporting Evidence: PMID:36917008 The IRF4 F359L and IRF4 WT proteins were similar with regard to their subcellular localization in the cytoplasm and the nucleus
GO:0005737 cytoplasm	IMP PMID:36917008 A neomorphic mutation in the interferon activation domain of...	ACCEPT	Summary: IMP annotation for cytoplasmic localization from the Thouenon et al. (2023) study. IRF4 is present in cytoplasm as well as nucleus. Reason: Cytoplasmic localization is confirmed by experimental evidence. IRF4 is likely present in the cytoplasm as a pre-nuclear pool or under conditions of cytoplasmic retention. This is consistent with UniProt subcellular localization annotation. Supporting Evidence: PMID:36917008 The IRF4 F359L and IRF4 WT proteins were similar with regard to their subcellular localization in the cytoplasm and the nucleus
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IMP PMID:29537367 IRF4 haploinsufficiency in a family with Whipple's disease.	ACCEPT	Summary: IMP annotation from Guerin et al. (2018) eLife, characterizing the IRF4 R98W variant in a family with Whipple's disease and IRF4 haploinsufficiency. The R98W mutation causes loss of DNA-binding transcription activator activity, and RC98-99AA double mutant also loses this activity. Reason: The loss-of-function analysis of the R98W disease variant provides direct evidence that wildtype IRF4 has DNA-binding transcription activator activity. The R98 residue is within the IRF DBD (aa 21-129) and is critical for DNA contact. Supporting Evidence: PMID:29537367 We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9907145	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9907145 (IRF4 binds the TYR promoter), placing IRF4 in the nucleoplasm where it binds the tyrosinase promoter in cooperation with MITF. Reason: Correct localization for a transcription factor binding a target promoter. The Reactome pathway describes IRF4's role in pigmentation gene regulation.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9907147	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9907147 (MITF-M-dependent IRF4 gene expression), placing IRF4 in the nucleoplasm. Reason: Correct annotation. IRF4 is expressed and functions in the nucleoplasm.
GO:0005515 protein binding	IPI PMID:33951726 Constrained chromatin accessibility in PU.1-mutated agammagl...	MODIFY	Summary: IPI annotation from Le Coz et al. (2021) J Exp Med, demonstrating that IRF4 directly interacts with PU.1 (SPI1). PU.1 mutations in agammaglobulinemia patients constrain chromatin accessibility. The interaction between PU.1 and IRF4 at EICE composite elements is a well-characterized functional partnership essential for B cell gene regulation. Reason: The interaction between IRF4 and PU.1/SPI1 is functionally critical and well-characterized, but "protein binding" is too vague. IRF4-PU.1 interaction at EICE elements is a core mechanism for IRF4 target gene selection in B cells. A more specific term describing transcription factor binding or DNA-binding transcription factor binding would be more informative. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:33951726 Consistent with intact PEST domains, all three proteins coimmunoprecipitated with IRF4 and IRF8 (Fig. S5 E).
GO:1990837 sequence-specific double-stranded DNA binding	IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ...	ACCEPT	Summary: IDA annotation from Yin et al. (2017) Science, a systematic analysis of DNA binding specificities of 542 human TFs using SELEX. IRF4 DNA binding specificity was characterized in this high-throughput but rigorous assay. Reason: This annotation is well-supported. The SELEX-based analysis provided direct experimental evidence for sequence-specific double-stranded DNA binding by IRF4. The study identified binding motifs for hundreds of TFs using purified proteins, providing direct biochemical evidence of IRF4's DNA binding activity. Supporting Evidence: PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences.
GO:0000785 chromatin	ISA GO_REF:0000113	ACCEPT	Summary: ISA annotation from TFClass database (tfclass:3.5.3), placing IRF4 at chromatin. As a DNA-binding transcription factor, IRF4 associates with chromatin at its target gene regulatory regions. Reason: Correct annotation. IRF4 binds chromatin at cis-regulatory elements of target genes. The TFClass-based annotation appropriately recognizes that sequence-specific DNA-binding TFs are located at chromatin.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific	ISA GO_REF:0000113	ACCEPT	Summary: ISA annotation from TFClass database classifying IRF4 as a sequence-specific DNA-binding transcription factor (class 3.5.3 - Tryptophan cluster factors: IRF subfamily). Reason: Correct annotation consistent with IRF4's classification as an IRF family transcription factor. This duplicates the IBA annotation but provides independent evidence from the TFClass classification system.
GO:0120162 positive regulation of cold-induced thermogenesis	ISS PMID:24995979 IRF4 is a key thermogenic transcriptional partner of PGC-1α.	KEEP AS NON CORE	Summary: ISS annotation based on mouse IRF4 ortholog (Q64287) data from PMID:24995979, transferred by YuBioLab. Mouse IRF4 promotes thermogenic gene expression in brown adipose tissue. Reason: This is the same annotation as the IEA Ensembl Compara transfer. While the mouse data supports a role for IRF4 in thermogenesis, this is clearly a non-core function for a protein primarily characterized as an immune system transcription factor. The human relevance is uncertain. Supporting Evidence: PMID:24995979 IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IDA PMID:12374808 Modulation of T cell cytokine production by interferon regul...	ACCEPT	Summary: IDA annotation from Hu et al. (2002) showing IRF4 binds to a specific site in the IL-4 promoter adjacent to an NFAT binding element, as demonstrated by EMSA and reporter assays in Jurkat T cells. Reason: Direct experimental evidence from EMSA showing IRF4 binds a specific DNA site in the IL-4 promoter. This is a core molecular function supported by detailed promoter analysis. Supporting Evidence: PMID:12374808 A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific	IDA PMID:12374808 Modulation of T cell cytokine production by interferon regul...	ACCEPT	Summary: IDA annotation from Hu et al. (2002) showing IRF4 transactivates luciferase reporter constructs driven by IL-2 and IL-4 promoters in Jurkat T cells. Stable IRF4 expression enhanced IL-2 synthesis and enabled production of IL-4, IL-10, and IL-13. Reason: Direct evidence that IRF4 functions as a transcriptional activator. This is the most specific appropriate MF term per GO-CAM TF annotation guidelines. The reporter assays directly demonstrate transcription activator activity. Supporting Evidence: PMID:12374808 Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:12374808 Modulation of T cell cytokine production by interferon regul...	ACCEPT	Summary: IDA annotation from Hu et al. (2002) demonstrating that IRF4 positively regulates Pol II transcription of cytokine genes in T cells, as shown by reporter assays and endogenous cytokine production measurements. Reason: Direct experimental evidence showing IRF4 activates transcription from IL-2 and IL-4 promoters. This biological process annotation is the appropriate complement to the MF annotation for transcription activator activity. Supporting Evidence: PMID:12374808 We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: HDA annotation from Ghosh et al. (2010), a proteomics study defining the membrane proteome of NK cells (YTS cell line). IRF4 was identified among 1843 proteins in membrane fractions. Reason: IRF4 is a nuclear transcription factor and not a membrane protein. Its detection in membrane fractions in this proteomics study likely represents contamination from nuclear/cytoplasmic fractions or transient association during cell lysis. The study itself notes that approximately 60% of identified proteins were not predicted membrane proteins. This annotation does not reflect a genuine biological function or localization of IRF4. Supporting Evidence: PMID:19946888 The remaining species were largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes.
GO:0005829 cytosol	TAS Reactome:R-HSA-1015702	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-1015702 (Expression of IFN-induced genes), placing IRF4 in the cytosol. This represents a Reactome model where IRF4 is produced in the cytosol before translocation to the nucleus. Reason: IRF4 is synthesized in the cytosol and can be found there. While its primary functional location is the nucleus, cytosolic localization is supported by UniProt and the Reactome pathway models. The cytosol annotation from Reactome likely represents the newly synthesized protein pool.
GO:0005829 cytosol	TAS Reactome:R-HSA-1031716	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-1031716 (Expression of IFNG-stimulated genes). Reason: Duplicate cytosol annotation from a different Reactome pathway. Acceptable as IRF4 is present in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-6790041	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-6790041 (Expression of STAT3-upregulated cytosolic proteins). Reason: Duplicate cytosol annotation from a Reactome pathway modeling STAT3-dependent IRF4 expression. Acceptable as IRF4 is present in the cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-9851117	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-9851117 (NPM1-ALK- and p-STAT3-dependent IRF4 gene expression). Reason: Duplicate cytosol annotation from a Reactome pathway modeling ALK-STAT3-dependent IRF4 expression in lymphoma contexts.
GO:0003700 DNA-binding transcription factor activity	ISS GO_REF:0000024	ACCEPT	Summary: Manual transfer from mouse IRF4 (Q64287) for DNA-binding transcription factor activity. Reason: Correct annotation. IRF4 is a DNA-binding transcription factor in both mouse and human. This broader term is a parent of the more specific GO:0000981 and GO:0001228 that are also annotated with stronger evidence.
GO:0042832 defense response to protozoan	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Manual transfer from mouse IRF4 for defense response to protozoan. Mouse Irf4-/- mice show impaired immune responses to Leishmania and Toxoplasma. Reason: Same annotation as the IEA Ensembl Compara transfer. IRF4 is required for effective immune responses against protozoan parasites through its role in T cell differentiation, but this is a downstream consequence rather than a core function.
GO:0043565 sequence-specific DNA binding	ISS GO_REF:0000024	ACCEPT	Summary: Manual transfer from mouse IRF4 for sequence-specific DNA binding. Reason: Correct and consistent with experimental evidence. IRF4 binds DNA in a sequence-specific manner through its tryptophan pentad repeat domain.
GO:0072540 T-helper 17 cell lineage commitment	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Manual transfer from mouse IRF4 for Th17 cell lineage commitment. Mouse Irf4-/- mice fail to develop Th17 cells. Reason: Same annotation as the IEA transfer. IRF4 is essential for Th17 differentiation, but this is one of several immune cell differentiation programs regulated by IRF4 and is a non-core annotation.
GO:0005634 nucleus	IC PMID:12374808 Modulation of T cell cytokine production by interferon regul...	ACCEPT	Summary: Curator inference that IRF4 is nuclear, based on evidence that it functions as a DNA-binding transcription factor (GO:0003700). Inferred from PMID:12374808 showing IRF4 transactivates promoter-reporter constructs and binds DNA. Reason: Logical inference that a DNA-binding transcription factor localizes to the nucleus. This is confirmed by direct evidence (IDA from HPA, IMP from PMID:36917008). Supporting Evidence: PMID:12374808 Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter.
GO:0032733 positive regulation of interleukin-10 production	IDA PMID:12374808 Modulation of T cell cytokine production by interferon regul...	KEEP AS NON CORE	Summary: Hu et al. (2002) showed that stable expression of IRF4 in Jurkat T cells enabled production of IL-10. IRF4 deficiency in mouse T cells profoundly impairs cytokine production. Reason: This is a legitimate downstream effect of IRF4 transcriptional activity in T cells. However, positive regulation of IL-10 production is a downstream consequence of IRF4's transcription factor activity rather than a core function. IRF4 likely activates IL-10 transcription indirectly through its effects on T cell differentiation programs. Supporting Evidence: PMID:12374808 We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13.
GO:0032736 positive regulation of interleukin-13 production	IDA PMID:12374808 Modulation of T cell cytokine production by interferon regul...	KEEP AS NON CORE	Summary: Hu et al. (2002) showed that stable expression of IRF4 in Jurkat T cells enabled production of IL-13. Reason: Legitimate downstream effect of IRF4 transcriptional activity. IL-13 production is enabled by IRF4 in the context of Th2 differentiation. This represents a specific downstream output of IRF4's transcription factor activity rather than a core molecular function. Supporting Evidence: PMID:12374808 We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13.
GO:0032743 positive regulation of interleukin-2 production	IDA PMID:12374808 Modulation of T cell cytokine production by interferon regul...	KEEP AS NON CORE	Summary: Hu et al. (2002) showed that stable IRF4 expression in Jurkat T cells strongly enhanced IL-2 synthesis. IRF4 transactivates luciferase reporters driven by the human IL-2 promoter. Reason: Legitimate downstream effect of IRF4 transcriptional activity. IL-2 is a direct transcriptional target of IRF4, as shown by promoter-reporter assays. While this is a more direct relationship than some other cytokine regulation annotations, it represents a specific downstream output of IRF4's core transcription factor activity rather than the core function itself. Supporting Evidence: PMID:12374808 We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13.
GO:0032753 positive regulation of interleukin-4 production	IDA PMID:12374808 Modulation of T cell cytokine production by interferon regul...	KEEP AS NON CORE	Summary: Hu et al. (2002) showed that stable IRF4 expression in Jurkat T cells enabled production of IL-4. IRF4 transactivates the IL-4 promoter and binds a site adjacent to an NFAT element, cooperating with NFATc1. Reason: Legitimate and well-supported downstream effect. IRF4 directly binds and activates the IL-4 promoter. This is a specific and well-characterized output of IRF4's transcription factor activity in the context of Th2 differentiation. Kept as non-core because it represents one specific target gene regulation downstream of the core TF activity. Supporting Evidence: PMID:12374808 A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1.
GO:0042110 T cell activation	NAS PMID:12374808 Modulation of T cell cytokine production by interferon regul...	KEEP AS NON CORE	Summary: NAS annotation from Hu et al. (2002) for T cell activation. The paper discusses IRF4's role in modulating T cell cytokine production, noting that IRF4 deficiency impairs mature CD4+ T cell function. Reason: IRF4 is important for T cell activation and function, but this is a downstream organismal process rather than a direct molecular activity. The NAS evidence code indicates this is based on statements in the paper rather than direct experimental demonstration in this study. T cell activation is a broad term encompassing many steps, and IRF4 contributes primarily through its transcriptional programs that enable cytokine production. Supporting Evidence: PMID:12374808 Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4(+) T cells to produce cytokines.
GO:0045622 regulation of T-helper cell differentiation	NAS PMID:12374808 Modulation of T cell cytokine production by interferon regul...	ACCEPT	Summary: NAS annotation for regulation of T-helper cell differentiation based on Hu et al. (2002). The paper discusses how IRF4 controls T cell cytokine production, which is closely linked to Th cell differentiation programs. Reason: IRF4 is genuinely critical for T-helper cell differentiation, including Th2, Th9, and Th17 lineages. While the evidence code is NAS (non-traceable author statement), this function is extremely well-established in subsequent literature. IRF4 is a master regulator of multiple Th cell differentiation programs. Supporting Evidence: PMID:12374808 These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines.
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:12374808 Modulation of T cell cytokine production by interferon regul...	ACCEPT	Summary: IDA annotation from Hu et al. (2002) showing IRF4 positively regulates DNA-templated transcription. Demonstrated by transactivation of IL-2 and IL-4 promoter-reporter constructs and enhancement of endogenous cytokine gene expression. Reason: Direct experimental evidence supporting IRF4 as a positive regulator of transcription. This is a core biological process annotation complementing the MF transcription activator annotations. Supporting Evidence: PMID:12374808 Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter.
GO:1900100 positive regulation of plasma cell differentiation	NAS PMID:29537367 IRF4 haploinsufficiency in a family with Whipple's disease.	NEW	Summary: IRF4 is essential for plasma cell differentiation. Loss-of-function variants in IRF4 cause combined immunodeficiency (IMD131) characterized by low immunoglobulin levels and low plasma cell counts (PMID:29537367, PMID:36662884, PMID:36917008). IRF4 cooperates with BLIMP1/XBP1 to drive the plasma cell differentiation program. In multiple myeloma, IRF4 is a lineage addiction factor for malignant plasma cells. Reason: This is a major gap in the current annotation set. Plasma cell differentiation is one of the best-established and most important biological functions of IRF4, yet it is not annotated. Human genetic evidence from IMD131 patients directly demonstrates IRF4's requirement for plasma cell differentiation. The Reactome and UniProt entries both reference IRF4's role in B cell/plasma cell biology. Supporting Evidence: PMID:29537367 AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance. PMID:36917008 Expression of the mutant IRF4 protein in control lymphoblastoid B cell lines reduced the expression of BLIMP-1 and XBP1 (key transcription factors in plasma cell differentiation).

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

📄 View Raw YAML