IRF8

Summary

IRF8 (interferon regulatory factor 8, HGNC:5358) is a protein-coding gene on chromosome 16q24.1, encoding Interferon regulatory factor 8 (Q02556). Transcription factor that specifically binds to the upstream regulatory region of type I interferon (IFN) and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)).

Interferon consensus sequence-binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-alpha and IFN-beta. IRF family proteins also control expression of IFN-alpha and IFN-beta-regulated genes that are induced by viral infection.

Source: NCBI Gene 3394 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 92
• Clinical variants (ClinVar): 439 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 29
• Transcription factor: yes — 74 downstream targets (CollecTRI)
• MANE Select transcript: NM_002163

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5358
Approved symbol	IRF8
Name	interferon regulatory factor 8
Location	16q24.1
Locus type	gene with protein product
Status	Approved
Aliases	IRF-8, ICSBP
Ensembl gene	ENSG00000140968
Ensembl biotype	protein_coding
OMIM	601565
Entrez	3394

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 18 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000268638, ENST00000562492, ENST00000563180, ENST00000564056, ENST00000564617, ENST00000564803, ENST00000565552, ENST00000566369, ENST00000569145, ENST00000569607, ENST00000570088, ENST00000696884, ENST00000696885, ENST00000696886, ENST00000696887, ENST00000696888, ENST00000696889, ENST00000696890, ENST00000859220, ENST00000859221, ENST00000859222, ENST00000955394, ENST00000955395, ENST00000955396, ENST00000955397, ENST00000955398

RefSeq mRNA: 3 — MANE Select: NM_002163 NM_001363907, NM_001363908, NM_002163

CCDS: CCDS10956, CCDS86547

Canonical transcript exons

ENST00000268638 — 9 exons

Exon	Start	End
ENSE00000945814	85913131	85913236
ENSE00000945819	85903015	85903189
ENSE00003458525	85908990	85909173
ENSE00003583152	85911570	85911658
ENSE00003968766	85899162	85899223
ENSE00003968771	85920109	85920224
ENSE00003968776	85921106	85922606
ENSE00003968778	85918417	85918803
ENSE00003968780	85914473	85914520

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 98.65.

FANTOM5 (CAGE): breadth broad, TPM avg 44.4480 / max 3592.7010, expressed in 629 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155427	43.5574	619
155430	0.4638	78
155433	0.1287	39
155436	0.0871	49
155434	0.0869	35
207994	0.0459	21
207993	0.0228	4
155429	0.0216	3
155431	0.0191	4
155432	0.0149	7

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.65	gold quality
mononuclear cell	CL:0000842	98.55	gold quality
leukocyte	CL:0000738	98.36	gold quality
lymph node	UBERON:0000029	98.01	gold quality
spleen	UBERON:0002106	97.45	gold quality
secondary oocyte	CL:0000655	97.34	gold quality
vermiform appendix	UBERON:0001154	97.12	gold quality
oocyte	CL:0000023	96.67	gold quality
granulocyte	CL:0000094	95.48	gold quality
caecum	UBERON:0001153	94.32	gold quality
blood	UBERON:0000178	93.43	gold quality
colonic epithelium	UBERON:0000397	93.29	gold quality
bone marrow	UBERON:0002371	92.80	gold quality
rectum	UBERON:0001052	92.67	gold quality
trabecular bone tissue	UBERON:0002483	92.20	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.06	gold quality
epithelium of nasopharynx	UBERON:0001951	92.04	gold quality
nasopharynx	UBERON:0001728	92.02	gold quality
duodenum	UBERON:0002114	91.54	gold quality
bone marrow cell	CL:0002092	91.33	gold quality
small intestine	UBERON:0002108	91.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.04	gold quality
mucosa of transverse colon	UBERON:0004991	89.98	gold quality
colonic mucosa	UBERON:0000317	89.84	gold quality
lower lobe of lung	UBERON:0008949	89.77	gold quality
ileal mucosa	UBERON:0000331	89.72	gold quality
jejunal mucosa	UBERON:0000399	89.57	gold quality
superficial temporal artery	UBERON:0001614	89.04	gold quality
gall bladder	UBERON:0002110	88.85	gold quality
tonsil	UBERON:0002372	88.47	gold quality

Single-cell (SCXA)

Detected in 37 experiment(s), a significant marker in 37.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	3719.72
E-MTAB-8498	yes	3389.19
E-GEOD-150728	yes	3190.66
E-GEOD-89232	yes	2292.04
E-MTAB-10432	yes	2013.60
E-CURD-6	yes	1831.69
E-CURD-122	yes	1652.65
E-MTAB-9067	yes	1604.31
E-MTAB-9906	yes	1527.56
E-MTAB-8530	yes	1440.76
E-CURD-79	yes	1396.18
E-CURD-55	yes	1392.97
E-CURD-112	yes	1390.18
E-MTAB-6505	yes	1367.14
E-MTAB-6653	yes	1227.33

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

74 targets.

Target	Regulation
ABL1
ACOT11
ARG1
BAX
BCL2	Repression
BCL2L1	Unknown
BCL6	Activation
BCR
C1QB
CCL5	Activation
CD68	Repression
CFLAR	Unknown
CHRNA1
CIITA
CREBBP
CTLA4
CXCL14	Repression
CXCL9	Activation
CYBB	Activation
DAB2
FANCF	Activation
FAP
FAS	Activation
FGFR1
GAS2	Repression
GNAS
GSTP1
HLA-B	Repression
IFNA1	Activation
IFNA4	Activation

JASPAR motifs

Motif	Name	Family
MA0652.1	IRF8	Interferon-regulatory factors
MA0652.2	IRF8	Interferon-regulatory factors

JASPAR matrix evidence (PMIDs): PMID:21731497

Upstream regulators (CollecTRI, top): BCL6, DNMT1, DNMT3B, GATA1, HAND1, IRF1, IRF5, IRF6, IRF8, MBD1, MED1, NCOA3, NFKB1, NR3C1, SPI1, STAT1, STAT5A, WT1

miRNA regulators (miRDB)

88 targeting IRF8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-6508-5P	99.92	70.67	2465

Literature-anchored findings (GeneRIF, showing 40)

• ICSBP1 activates transcription of the gene encoding neurofibromin 1 (PMID:15371411)
• interleukin-12 p35 gene transcription is activated by interferon regulatory factor-1 and interferon consensus sequence-binding protein (PMID:15489234)
• proteasomal degradation of IRF-8 mediated by the ubiquitin E3 ligase Cbl down-regulates IL-12 expression (PMID:15837792)
• the interaction of IRF-8 with TRAF6 modulates TLR signaling and may contribute to the cross-talk between IFN-gamma and TLR signal pathways (PMID:16484229)
• ICSBP tyrosine phosphorylation is necessary for the activation of NF1 transcription. ICSBP is a substrate for SHP2 protein tyrosine phosphatase (SHP2-PTP). (PMID:16914719)
• Our data suggest that ATRA-induced regulation of Stat2, ICSBP and C/EBPepsilon is dependent on active Stat1, and that a failure to correctly regulate these transcription factors is associated with the inhibition of monocytic differentiation. (PMID:16918696)
• IRF8 cooperates with PU.1 and IRF-2 to activate a composite ets/IRF-cis element in the NF1 promoter. The conserved IRF domain tyrosine in ICSBP/IRF8 is required for interaction with the DNA-bound PU.1-IRF2 heterodimer. (PMID:17200120)
• IRF8 is involved in a cooperative interaction with transcription factors Spi-1/PU.1 and non-tyrosine phosphorylated Stat1 in the formation of a pre-associated, poised complex for interleukin 1-beta gene induction. (PMID:17386941)
• this CHRNA1 variant prevents binding of interferon regulatory factor 8 (IRF8) and abrogates CHRNA1 promoter activity in thymic epithelial cells in vitro (PMID:17687331)
• The interferon consensus sequence-binding protein (ICSBP/IRF8) represses PTPN13 gene transcription in differentiating myeloid cells (PMID:18195016)
• activation of SHP2 protein tyrosine phosphatase synergized with ICSBP haploinsufficiency to facilitate cytokine-induced myeloproliferation, apoptosis resistance, and rapid progression to AML in a murine bone marrow transplantation model. (PMID:18246201)
• Dendritic cell priming by L. major infection results in the early activation of NF-kappaB transcription factors and the up-regulation and nuclear translocation of interferon regulatory factor 1 (IRF-1) and IRF-8. (PMID:18316378)
• IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas (PMID:18469857)
• Suggest role for IRF8 during germinal center B-cell development and in related lymphomas, and provide a new diagnostic marker helpful in distinguishing B-cell non-Hodgkin lymphoma subtypes. (PMID:18580679)
• Age-associated expression changes of IRF8 protein and mRNA levels in PB CD34+ cells (PMID:18596738)
• Pint mutations in patients with type 2 diabetes and their families were studied. mitochondrial genes including np3316, np3394 and np3426 in the ND1 region and np3243 in the tRNA(Leu(UUR))were screened. (PMID:18701018)
• silencing of ICSBP/IRF8 expression, by DNA methylation or other epigenetic mechanisms, may be associated with the malignant phenotype of MM. (PMID:18922617)
• colon carcinoma cells silence IFN-gamma-activated IRF8 expression through MBD1-dependent and PIAS1-mediated inhibition of pSTAT1 function at the methylated IRF8 promoter (PMID:19074829)
• Replication in an independent set of 2,215 subjects with multiple sclerosis (MS) and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A, IRF8 and CD6; TNFRSF1A harbors two independent susceptibility alleles. (PMID:19525953)
• Increased expression of IRF-8 in tumor-induced CD11b-positive/Gr-1-positive cells exerts an antitumor rather than protumorigenic effect in tumor-bearing IRF-8-transgenic hybrid mice. (PMID:19542426)
• Data identify the gene encoding Fanconi F (FANCF) as an ICSBP target gene. (PMID:19801548)
• IL-27 p28 gene transcription is activated by interferon regulatory factor 8 in cooperation with interferon regulatory factor 1 (PMID:20435892)
• IRF8 and PU.1 can have both combined, and independent actions on different promoters in myeloid cells. (PMID:20573402)
• The chromatin modifications were determined at five PRC2 targets commonly underexpressed in multiple myeloma (CIITA, CXCL12, GATA2, CDH6 and ICSBP/IRF8). The selected genes were confirmed to be underexpressed in MM compared to normal plasma cells. (PMID:20634887)
• Studies have identified a Gas2/calpain-dependent mechanism by which ICSBP influences beta-catenin activity in myeloid leukemia. (PMID:20679491)
• independent association of 4 SNPs that met genome-wide statistical significance within the IRF8 gene in familial chronic lymphocytic leukemia (PMID:21131588)
• IRF8 is required for normal development of marginal zone (MZ) and follicular B cells. Mice with a conventional knockout of Irf8 or a point mutation in the IRF association domain of IRF8 have increased numbers of MZ B cells. (PMID:21178004)
• Positive regulatory domain I (PRDM1) and IRF8/PU.1 counter-regulate MHC class II transactivator (CIITA) expression during dendritic cell maturation. (PMID:21216962)
• IRF-8 is a key player in the control of intracellular viral dsRNA-induced responses by a mechanism that negatively regulates Toll-like receptor (TLR)3 expression and can be exploited to block excessive TLR activation. (PMID:21220691)
• we propose a model for the rapid induction of IFN-beta in monocytes, whereby IRF8 and PU.1 form a scaffold complex on the IFN-beta promoter to facilitate the recruitment of IRF3 (PMID:21228327)
• The promoter was methylated in many MDS or AML patients. This may be the main mechanism of ICSBP inactivation in myeloid malignancies & may be functionally important for accumulation of chromosome aberrations during leukemic progression. (PMID:21475251)
• Findings determine the mechanism of IRF8 downregulation in CML cells. (PMID:21487040)
• We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both mutations impair IRF8 transcriptional activity. (PMID:21524210)
• association of single nucleotide polymorphisms to multiple sclerosis (PMID:21552549)
• study identifies a novel role for ICSBP in regulating cell growth via TGF-beta receptor upregulation and subsequent activation of the TGF-beta receptor/TAK-1/p38 pathway (PMID:21625229)
• IRF4 has activities similar to IRF8 in regulating myeloid cell development (PMID:22003407)
• Association analysis identified five SLE susceptibility genes reaching genome-wide levels of significance : NCF2 ,IKZF1 ,IRF8 ,IFIH1 , and TYK2 (PMID:22046141)
• [review] Induction of transcriptional repressors such as IRF8 is one of the mechanisms that inhibits osteoclastogenesis. (PMID:22082370)
• Data showed that IRF8 target genes contributes to multiple aspects of the biology of mature B cells including critical components of the molecular crosstalk among GC B cells, T follicular helper cells, and follicular dendritic cells. (PMID:22096565)
• interaction between Tel and Tel-PdgfRbeta decreases Tel/Icsbp/Hdac3 binding to the PTPN13 cis element, resulting in increased transcription. (PMID:22262849)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	irf8	ENSDARG00000056407
mus_musculus	Irf8	ENSMUSG00000041515
rattus_norvegicus	Irf8	ENSRNOG00000017869

Paralogs (8): IRF6 (ENSG00000117595), IRF1 (ENSG00000125347), IRF3 (ENSG00000126456), IRF5 (ENSG00000128604), IRF4 (ENSG00000137265), IRF2 (ENSG00000168310), IRF7 (ENSG00000185507), IRF9 (ENSG00000213928)

Protein

Protein identifiers

Interferon regulatory factor 8 — Q02556 (reviewed: Q02556)

Alternative names: Interferon consensus sequence-binding protein

All UniProt accessions (10): Q02556, A0A8Q3SJ00, A0A8Q3SJ42, H3BNX4, H3BQF9, H3BQH6, H3BQK3, H3BRT4, H3BT31, H3BVC2

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that specifically binds to the upstream regulatory region of type I interferon (IFN) and IFN-inducible MHC class I genes (the interferon consensus sequence (ICS)). Can both act as a transcriptional activator or repressor. Plays a negative regulatory role in cells of the immune system. Involved in CD8(+) dendritic cell differentiation by forming a complex with the BATF-JUNB heterodimer in immune cells, leading to recognition of AICE sequence (5’-TGAnTCA/GAAA-3’), an immune-specific regulatory element, followed by cooperative binding of BATF and IRF8 and activation of genes. Required for the development of plasmacytoid dendritic cells (pDCs), which produce most of the type I IFN in response to viral infection. Positively regulates macroautophagy in dendritic cells. Acts as a transcriptional repressor of osteoclast differentiation factors such as NFATC1 and EEIG1.

Subunit / interactions. Interacts (via C-terminus) with TRIM21 (via C-terminus). Interacts with the BATF-JUNB heterodimer. Interacts with BATF (via bZIP domain); the interaction is direct. Interacts with COPS2. Interacts with SPI1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Predominantly expressed in lymphoid tissues.

Post-translational modifications. Ubiquitinated. Ubiquitination by TRIM21 in macrophages, a process that is strongly increased upon interferon gamma stimulation, leds to the enhanced transcriptional activity of target cytokine genes. Ubiquitination leads to its degradation by the proteasome. Sumoylated with SUMO3. Desumoylated by SENP1.

Disease relevance. Immunodeficiency 32A (IMD32A) [MIM:614893] An immunologic disorder characterized by abnormal peripheral blood myeloid phenotype with a marked loss of CD11C-positive/CD1C dendritic cells, resulting in selective susceptibility to mycobacterial infections. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 32B (IMD32B) [MIM:226990] An autosomal recessive primary immunodeficiency characterized by monocyte and dendritic cell deficiency, myeloproliferation, and susceptibility to severe opportunistic infections, including disseminated BCG infection and oral candidiasis. The disease is caused by variants affecting the gene represented in this entry.

Induction. By IFNG/IFN-gamma. Negatively regulated by microRNA-155 (miR155).

Similarity. Belongs to the IRF family.

RefSeq proteins (3): NP_001350836, NP_001350837, NP_002154* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001346	Interferon_reg_fact_DNA-bd_dom	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR017855	SMAD-like_dom_sf	Homologous_superfamily
IPR019471	Interferon_reg_factor-3	Domain
IPR019817	Interferon_reg_fac_CS	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00605, PF10401

UniProt features (9 total): sequence variant 4, mutagenesis site 3, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02556-F1	75.54	0.53

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (3):

Position	Phenotype
108	in resting macrophages, no effect on cytoplasmic subcellular localization. decreased nuclear subcellular localization up
108	in resting macrophages, no effect on cytoplasmic subcellular localization. loss of nuclear subcellular localization upon
108	in resting macrophages, no effect on cytoplasmic subcellular localization. no effect on nuclear subcellular localization

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-877300	Interferon gamma signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-913531	Interferon Signaling

MSigDB gene sets: 534 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_DENDRITIC_CELL_DIFFERENTIATION, MCLACHLAN_DENTAL_CARIES_UP, LU_IL4_SIGNALING, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, HOFMANN_CELL_LYMPHOMA_UP, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, NIKOLSKY_OVERCONNECTED_IN_BREAST_CANCER, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN

GO Biological Process (24): negative regulation of transcription by RNA polymerase II (GO:0000122), plasmacytoid dendritic cell differentiation (GO:0002273), germinal center B cell differentiation (GO:0002314), follicular B cell differentiation (GO:0002316), immune system process (GO:0002376), regulation of transcription by RNA polymerase II (GO:0006357), phagocytosis (GO:0006909), autophagy (GO:0006914), immune response (GO:0006955), myeloid cell differentiation (GO:0030099), regulation of type I interferon production (GO:0032479), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-12 production (GO:0032735), defense response to bacterium (GO:0042742), defense response to protozoan (GO:0042832), positive regulation of apoptotic process (GO:0043065), positive regulation of transcription by RNA polymerase II (GO:0045944), cellular response to lipopolysaccharide (GO:0071222), cellular response to type II interferon (GO:0071346), dendritic cell differentiation (GO:0097028), regulation of DNA-templated transcription (GO:0006355), response to bacterium (GO:0009617), positive regulation of DNA-templated transcription (GO:0045893), defense response to other organism (GO:0098542)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Interferon Signaling	2
Immune System	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
mature B cell differentiation involved in immune response	2
regulation of DNA-templated transcription	2
positive regulation of cytokine production	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
plasmacytoid dendritic cell activation	1
dendritic cell differentiation	1
biological_process	1
endocytosis	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
immune system process	1
response to stimulus	1
hemopoiesis	1
cell differentiation	1
regulation of cytokine production	1
type I interferon production	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
defense response	1
response to bacterium	1
response to protozoan	1
defense response to other organism	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
positive regulation of DNA-templated transcription	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to type II interferon	1
cellular response to cytokine stimulus	1

Protein interactions and networks

STRING

3468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRF8	SPI1	P17947	998
IRF8	IRF1	P10914	947
IRF8	IFNG	P01579	846
IRF8	SPIB	Q01892	805
IRF8	BATF3	Q9NR55	796
IRF8	STAT1	P42224	796
IRF8	RUNX1	Q01196	785
IRF8	TRAF6	Q9Y4K3	778
IRF8	NFATC1	O95644	764
IRF8	TRIM21	P19474	749
IRF8	IFNB1	P01574	748
IRF8	MAFB	Q9Y5Q3	746
IRF8	FOS	P01100	736
IRF8	ISG15	P05161	721
IRF8	BATF	Q16520	718

IntAct

15 interactions, top by confidence:

A	B	Type	Score
IRF8	OPTN	psi-mi:“MI:0915”(physical association)	0.560
IRF6	IRF8	psi-mi:“MI:0914”(association)	0.500
IRF8	IRF6	psi-mi:“MI:0914”(association)	0.500
IRF8	IRF6	psi-mi:“MI:0915”(physical association)	0.500
IRF8	HSPE1	psi-mi:“MI:0915”(physical association)	0.400
IFNA10	IRF8	psi-mi:“MI:0915”(physical association)	0.370
TNFSF10	IRF8	psi-mi:“MI:0915”(physical association)	0.370
IRF8	FLOT1	psi-mi:“MI:0914”(association)	0.350
CA10	ENTPD5	psi-mi:“MI:0914”(association)	0.350
IRF8	BCL9	psi-mi:“MI:2364”(proximity)	0.270
IRF8		psi-mi:“MI:0915”(physical association)	0.000
IRF8	flaS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (71): USP4 (Affinity Capture-Western), IRF8 (Affinity Capture-Western), IRF8 (Reconstituted Complex), IRF8 (Protein-RNA), IRF8 (Proximity Label-MS), COPS2 (Two-hybrid), IRF8 (Reconstituted Complex), COPS2 (Affinity Capture-Western), IRF1 (Two-hybrid), IRF8 (Reconstituted Complex), IRF8 (Reconstituted Complex), IRF1 (Affinity Capture-Western), IRF2 (Affinity Capture-Western), HIVEP1 (Proximity Label-MS), FLI1 (Proximity Label-MS)

ESM2 similar proteins: A1L1K1, A2ARM1, A2AVJ5, A4IFC9, A7E305, G5EGQ2, O08653, O36006, O43435, O46080, O95343, P13481, P28702, P28704, P56423, P56424, P56645, P61260, P97499, Q02556, Q07820, Q2NL16, Q32N92, Q5E9R0, Q5REG4, Q5SQI0, Q5TJF7, Q5U2W6, Q5U2Y1, Q61010, Q62233, Q6MZQ0, Q80V91, Q86Y01, Q86YD1, Q8AW93, Q8BIG4, Q8HYS5, Q8N9I9, Q91VU8

Diamond homologs: A0FIN4, O14896, P10914, P14316, P15314, P23570, P23611, P23906, P56477, P70671, P97431, Q00978, Q02556, Q08DD6, Q13568, Q14653, Q15306, Q3SZP0, Q4JF28, Q58DJ0, Q61179, Q64287, Q764M6, Q8R4E0, Q90643, Q90871, Q90876, Q98925, Q92985, F5HF68, P70434

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
IRF8	“up-regulates quantity by expression”	CYBB	“transcriptional regulation”
IRF8	“up-regulates quantity by expression”	NCF2	“transcriptional regulation”
IRF1	“up-regulates activity”	IRF8	binding
SPI1	“up-regulates activity”	IRF8	binding
NCBP1	“up-regulates activity”	IRF8	binding
PTPN11	“down-regulates activity”	IRF8	dephosphorylation
TRIM21	“down-regulates quantity”	IRF8	ubiquitination
IRF8	“down-regulates quantity by repression”	CD68	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

439 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	220
Likely benign	180
Benign	22

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
4819872	NM_002163.4(IRF8):c.1134_1144del (p.Ala381fs)	Pathogenic
56842	NM_002163.4(IRF8):c.322A>G (p.Lys108Glu)	Pathogenic
56843	NM_002163.4(IRF8):c.238A>G (p.Thr80Ala)	Likely pathogenic
916562	NM_002163.4(IRF8):c.814G>A (p.Gly272Arg)	Likely pathogenic

SpliceAI

1409 predictions. Top by Δscore:

Variant	Effect	Δscore
16:85903012:A:AG	acceptor_gain	1.0000
16:85903012:AAG:A	acceptor_gain	1.0000
16:85903013:A:AG	acceptor_gain	1.0000
16:85903013:AG:A	acceptor_gain	1.0000
16:85903013:AGGAT:A	acceptor_gain	1.0000
16:85903014:G:GT	acceptor_gain	1.0000
16:85903014:GG:G	acceptor_gain	1.0000
16:85903014:GGA:G	acceptor_gain	1.0000
16:85903014:GGAT:G	acceptor_gain	1.0000
16:85903014:GGATG:G	acceptor_gain	1.0000
16:85903147:C:T	donor_gain	1.0000
16:85903166:G:GT	donor_gain	1.0000
16:85903185:TTAAG:T	donor_loss	1.0000
16:85903186:TAAG:T	donor_loss	1.0000
16:85903187:AAGGT:A	donor_loss	1.0000
16:85903189:GGTA:G	donor_loss	1.0000
16:85903190:GTA:G	donor_loss	1.0000
16:85903191:T:A	donor_loss	1.0000
16:85908985:TTCA:T	acceptor_loss	1.0000
16:85908986:TCA:T	acceptor_loss	1.0000
16:85908988:A:T	acceptor_loss	1.0000
16:85908988:AG:A	acceptor_gain	1.0000
16:85908989:GG:G	acceptor_gain	1.0000
16:85908989:GGCCT:G	acceptor_gain	1.0000
16:85909095:G:GT	donor_gain	1.0000
16:85909161:G:GT	donor_gain	1.0000
16:85909172:AT:A	donor_gain	1.0000
16:85909174:G:GG	donor_gain	1.0000
16:85911568:A:AG	acceptor_gain	1.0000
16:85911569:G:GG	acceptor_gain	1.0000

AlphaMissense

2799 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:85903044:T:A	L10H	1.000
16:85903044:T:C	L10P	1.000
16:85903052:T:A	W13R	1.000
16:85903052:T:C	W13R	1.000
16:85903053:G:C	W13S	1.000
16:85903054:G:C	W13C	1.000
16:85903054:G:T	W13C	1.000
16:85903056:T:C	L14P	1.000
16:85903065:A:C	Q17P	1.000
16:85903092:T:A	L26Q	1.000
16:85903092:T:C	L26P	1.000
16:85903097:T:A	W28R	1.000
16:85903097:T:C	W28R	1.000
16:85903099:G:C	W28C	1.000
16:85903099:G:T	W28C	1.000
16:85903122:T:C	F36S	1.000
16:85903125:G:C	R37P	1.000
16:85903128:T:A	I38N	1.000
16:85903128:T:C	I38T	1.000
16:85903128:T:G	I38S	1.000
16:85903133:T:A	W40R	1.000
16:85903133:T:C	W40R	1.000
16:85903134:G:C	W40S	1.000
16:85903135:G:C	W40C	1.000
16:85903135:G:T	W40C	1.000
16:85903136:A:G	K41E	1.000
16:85903137:A:C	K41T	1.000
16:85903137:A:T	K41I	1.000
16:85903138:A:C	K41N	1.000
16:85903138:A:T	K41N	1.000

dbSNP variants (sampled 300 via entrez): RS1000053323 (16:85922462 G>A), RS1000541441 (16:85903255 G>A), RS1000775681 (16:85900369 A>C,G), RS1000826362 (16:85920671 A>G), RS1000980366 (16:85914387 G>T), RS1001249223 (16:85922095 C>A), RS1001425980 (16:85898567 G>C), RS1001469234 (16:85900689 T>C), RS1001542547 (16:85921386 G>C), RS1001582116 (16:85900858 C>G), RS1001718088 (16:85916716 G>A), RS1001821192 (16:85922557 G>A,T), RS1001823857 (16:85916507 A>C), RS1001873466 (16:85922218 A>C,G), RS1002076573 (16:85905161 A>G)

Disease associations

OMIM: gene MIM:601565 | disease phenotypes: MIM:226990, MIM:614894, MIM:614893, MIM:189960

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 32B	Strong	Autosomal recessive
Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency	Strong	Autosomal dominant

Mondo (3): immunodeficiency 32B (MONDO:0009194), Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (MONDO:0013957), esophageal atresia/tracheoesophageal fistula (MONDO:0008586)

Orphanet (3): Chronic Epstein-Barr virus infection syndrome (Orphanet:2566), Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency (Orphanet:319600), Esophageal atresia (Orphanet:1199)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000246	Sinusitis
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001880	Increased total eosinophil count
HP:0001903	Anemia
HP:0001945	Fever
HP:0002090	Pneumonia
HP:0002110	Bronchiectasis
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002514	Cerebral calcification
HP:0002716	Lymphadenopathy
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0002840	Lymphadenitis
HP:0003073	Hypoalbuminemia
HP:0003203	Decreased neutrophil oxidative burst
HP:0003593	Infantile onset
HP:0010978	Abnormality of immune system physiology
HP:0011463	Childhood onset
HP:0011897	Increased total neutrophil count
HP:0012138	Granulocytic hyperplasia
HP:0012312	Decreased total monocyte count
HP:0020086	BCGitis
HP:0032252	Granuloma
HP:0410242	Abnormal circulating IgG concentration

GWAS associations

92 associations (top):

Study	Trait	p-value
GCST000424_10	Multiple sclerosis	4.000000e-09
GCST000906_1	Chronic lymphocytic leukemia	3.000000e-09
GCST001017_1	Diabetic retinopathy	3.000000e-06
GCST001160_5	Systemic sclerosis	2.000000e-12
GCST001198_26	Multiple sclerosis	1.000000e-08
GCST001454_15	Rheumatoid arthritis	2.000000e-06
GCST001725_53	Inflammatory bowel disease	1.000000e-09
GCST001887_4	Monocyte count	3.000000e-16
GCST001938_3	Ulcerative colitis	4.000000e-10
GCST002069_19	Systemic lupus erythematosus and Systemic sclerosis	3.000000e-10
GCST002073_21	Chronic lymphocytic leukemia	5.000000e-17
GCST002095_1	Major depressive disorder	3.000000e-07
GCST002299_19	Chronic lymphocytic leukemia	1.000000e-09
GCST002318_19	Rheumatoid arthritis	9.000000e-09
GCST002318_40	Rheumatoid arthritis	1.000000e-12
GCST003155_21	Systemic lupus erythematosus	1.000000e-17
GCST003156_36	Systemic lupus erythematosus	2.000000e-18
GCST003468_17	Chronic lymphocytic leukemia	1.000000e-22
GCST003599_15	Systemic lupus erythematosus	4.000000e-06
GCST003622_42	Systemic lupus erythematosus	5.000000e-17
GCST003688_2	Gestational age at birth (maternal effect)	5.000000e-06
GCST004099_13	B-cell malignancies (chronic lymphocytic leukemia, Hodgkin lymphoma or multiple myeloma) (pleiotropy)	7.000000e-07
GCST004146_20	Chronic lymphocytic leukemia	1.000000e-28
GCST004164_5	Monocyte count	8.000000e-06
GCST004608_206	Granulocyte percentage of myeloid white cells	2.000000e-98
GCST004608_207	Granulocyte percentage of myeloid white cells	5.000000e-83
GCST004608_208	Granulocyte percentage of myeloid white cells	5.000000e-205
GCST004608_209	Granulocyte percentage of myeloid white cells	8.000000e-131
GCST004608_210	Granulocyte percentage of myeloid white cells	2.000000e-77
GCST004608_211	Granulocyte percentage of myeloid white cells	6.000000e-137

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0005112	gestational age
EFO:0006921	birth measurement
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0008536	anti-centromere-antibody-positive systemic scleroderma
EFO:1001017	limited scleroderma
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004462	PR interval
EFO:0008343	sex interaction measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

59 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
Acetaminophen	increases expression	2
Arsenic	decreases expression, increases abundance, increases methylation	2
Nickel	increases expression	2
GSK-J4	decreases expression	1
TL8-506	affects cotreatment, increases expression	1
apocarotenal	increases expression	1
fulvic acid	affects cotreatment, decreases reaction, increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases methylation	1
terbufos	increases methylation	1
trichostatin A	affects reaction, affects expression, affects methylation	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
nickel chloride	affects cotreatment, increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentanal	increases expression	1
CGP 52608	increases reaction, affects binding	1
abrine	increases expression	1
gardiquimod	increases expression, decreases reaction	1
MK 2206	decreases expression, decreases reaction, increases expression	1
MK-8776	increases expression	1
(+)-JQ1 compound	affects binding, decreases reaction, decreases expression	1
Calcimycin	affects cotreatment, decreases reaction, increases expression	1
Aripiprazole	affects cotreatment, decreases expression	1
Decitabine	affects methylation, affects reaction, affects expression	1
Zoledronic Acid	decreases expression	1

Cellosaurus cell lines

9 cell lines: 4 embryonic stem cell, 3 induced pluripotent stem cell, 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A3H1	SEES3-1V human IRF8, clone1	Embryonic stem cell	Male
CVCL_A3H2	SEES3-1V human IRF8, clone2	Embryonic stem cell	Male
CVCL_A3H3	SEES3-1V human IRF8, clone3	Embryonic stem cell	Male
CVCL_A5GQ	UKAi001-A-1	Induced pluripotent stem cell	Male
CVCL_A5GR	UKAi001-B-1	Induced pluripotent stem cell	Male
CVCL_A5GS	UKAi001-C-1	Induced pluripotent stem cell	Male
CVCL_C3LB	ESIBIe003-A-7	Embryonic stem cell	Female
CVCL_F1QK	HyCyte HK-2 KO-hIRF8	Transformed cell line	Male
CVCL_ST03	HAP1 IRF8 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

13 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05384743	PHASE3	UNKNOWN	Rituximab Monotherapy for EBV-HLH and CAEBV
NCT01998633	PHASE2	COMPLETED	Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
NCT07381738	PHASE2	RECRUITING	Unrelated Cord Blood Transplantation for EBV-associated Lymphoproliferative Disorders
NCT06666153	PHASE1	NOT_YET_RECRUITING	Clinical Study of Therapeutic Immunological Agent for EBV Lymphoproliferative Diseases
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT05236764	Not specified	ACTIVE_NOT_RECRUITING	Haploidentical Hematopoietic Cell Transplantation Using TCR Alpha/Beta and CD19 Depletion
NCT05532826	Not specified	UNKNOWN	Clinical Study of Donor EBV-CTL Infusion in Patients With CAEBV and EBV-HLH After Allo-HSCT
NCT05841342	Not specified	UNKNOWN	Prospective Study of Immune Function and PD-1 Antibody Therapy Efficacy Predictors on CAEBV and EBV-HLH Patients
NCT06491719	Not specified	NOT_YET_RECRUITING	A Study on Efficacy and Safety of iNK Cells for CAEBV /EBV-HLH After Allo-HSCT
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair