IRF5

Summary

IRF5 (interferon regulatory factor 5, HGNC:6120) is a protein-coding gene on chromosome 7q32.1, encoding Interferon regulatory factor 5 (Q13568). Transcription factor that plays a critical role in innate immunity by activating expression of type I interferon (IFN) IFNA and INFB and inflammatory cytokines downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9.

This gene encodes a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Alternative promoter use and alternative splicing result in multiple transcript variants, and a 30-nt indel polymorphism (SNP rs60344245) can result in loss of a 10-aa segment.

Source: NCBI Gene 3663 — RefSeq curated summary.

At a glance

• Gene–disease (curated): systemic lupus erythematosus (Supportive, GenCC)
• GWAS associations: 75
• Clinical variants (ClinVar): 86 total — 1 likely-pathogenic
• Phenotypes (HPO): 112
• Transcription factor: yes — 39 downstream targets (CollecTRI)
• MANE Select transcript: NM_001098629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6120
Approved symbol	IRF5
Name	interferon regulatory factor 5
Location	7q32.1
Locus type	gene with protein product
Status	Approved
Aliases	IRF-5
Ensembl gene	ENSG00000128604
Ensembl biotype	protein_coding
OMIM	607218
Entrez	3663

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 23 protein_coding, 7 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000357234, ENST00000402030, ENST00000461416, ENST00000464557, ENST00000465603, ENST00000467002, ENST00000473745, ENST00000473787, ENST00000477535, ENST00000479582, ENST00000488569, ENST00000489702, ENST00000650798, ENST00000652142, ENST00000652525, ENST00000700148, ENST00000700149, ENST00000700150, ENST00000700151, ENST00000700152, ENST00000700153, ENST00000700154, ENST00000898739, ENST00000898740, ENST00000898741, ENST00000898742, ENST00000898743, ENST00000898744, ENST00000898745, ENST00000898746, ENST00000898747, ENST00000956592, ENST00000956593, ENST00000956594

RefSeq mRNA: 7 — MANE Select: NM_001098629 NM_001098627, NM_001098629, NM_001098630, NM_001242452, NM_001347928, NM_001364314, NM_032643

CCDS: CCDS43645, CCDS56512, CCDS5808

Canonical transcript exons

ENST00000357234 — 9 exons

Exon	Start	End
ENSE00001478273	128947230	128947535
ENSE00003525390	128946501	128946562
ENSE00003531764	128947023	128947056
ENSE00003542241	128948210	128948328
ENSE00003580979	128947729	128948121
ENSE00003601547	128942071	128942276
ENSE00003604260	128945845	128946034
ENSE00003846160	128937927	128938049
ENSE00003846269	128948573	128950038

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 96.63.

FANTOM5 (CAGE): breadth broad, TPM avg 6.3478 / max 188.4171, expressed in 802 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80995	5.2885	790
80994	0.4226	42
80999	0.1417	68
80996	0.1377	73
81001	0.0871	33
80997	0.0862	23
80993	0.0724	33
80998	0.0570	19
81000	0.0546	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.63	gold quality
mononuclear cell	CL:0000842	96.20	gold quality
granulocyte	CL:0000094	96.16	gold quality
leukocyte	CL:0000738	96.02	gold quality
metanephros cortex	UBERON:0010533	90.69	gold quality
spleen	UBERON:0002106	89.92	gold quality
blood	UBERON:0000178	89.03	gold quality
bone marrow cell	CL:0002092	87.39	gold quality
lower esophagus mucosa	UBERON:0035834	87.39	gold quality
lymph node	UBERON:0000029	85.34	gold quality
esophagus mucosa	UBERON:0002469	85.06	gold quality
triceps brachii	UBERON:0001509	83.97	gold quality
upper lobe of left lung	UBERON:0008952	83.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.00	gold quality
upper lobe of lung	UBERON:0008948	82.65	gold quality
gluteal muscle	UBERON:0002000	82.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.41	gold quality
right uterine tube	UBERON:0001302	81.77	gold quality
right coronary artery	UBERON:0001625	81.62	gold quality
vermiform appendix	UBERON:0001154	80.84	gold quality
bone marrow	UBERON:0002371	80.80	gold quality
small intestine	UBERON:0002108	80.53	gold quality
skin of abdomen	UBERON:0001416	80.50	gold quality
endometrium epithelium	UBERON:0004811	80.42	silver quality
seminal vesicle	UBERON:0000998	80.08	gold quality
minor salivary gland	UBERON:0001830	80.06	gold quality
skin of leg	UBERON:0001511	80.04	gold quality
gall bladder	UBERON:0002110	80.04	gold quality
right lung	UBERON:0002167	79.99	gold quality
adult mammalian kidney	UBERON:0000082	79.85	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.70
E-MTAB-5061	no	3.75

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

39 targets.

Target	Regulation
CCL1	Activation
CCL19	Activation
CCL2	Activation
CCL3	Repression
CCL4	Activation
CCL5	Activation
CDKN1A	Unknown
CXCL10	Activation
CXCL8	Activation
IFN1@
IFNA1	Activation
IFNA10	Activation
IFNA13	Activation
IFNA14	Activation
IFNA17	Activation
IFNA2	Activation
IFNA21	Activation
IFNA4	Activation
IFNA5	Activation
IFNA8	Activation
IFNB1	Activation
IFNG
IKZF1	Unknown
IL10	Unknown
IL12A	Activation
IL12B	Activation
IL1B	Unknown
IL6	Activation
IRF4
IRF5

JASPAR motifs

Motif	Name	Family
MA1420.1	IRF5	Interferon-regulatory factors

JASPAR matrix evidence (PMIDs): PMID:25896227

Upstream regulators (CollecTRI, top): IRF3, IRF4, IRF5, IRF8, PITX2, SP1, STAT5A, TP53, TP73

miRNA regulators (miRDB)

61 targeting IRF5, 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-5193	100.00	67.26	1744
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-4755-3P	98.77	65.59	1915

Literature-anchored findings (GeneRIF, showing 40)

• this study defines the regulatory phosphorylation sites that control the activity of IRF-5 in Newcastle disease virus-infected cells and provides further insight into its structure and function (PMID:12138184)
• IRF-5 can act as both an activator and a repressor of interferon gene induction dependent on the IRF-interacting partner, and IRF-5 may be a part of the regulatory network that ensures timely expression of the immediate early inflammatory genes (PMID:12600985)
• IRF-5 is a downstream target of p53and its growth inhibitory and proapoptotic effects are independent of p53. (PMID:14559832)
• IRF-5-and IRF-7-induced innate antiviral response results in a broad alteration of the transcriptional profile of cellular genes (PMID:15308637)
• CRM1-dependent nuclear export pathway is involved in the regulation of IRF-5 subcellular localization (PMID:15556946)
• identified IRF5 SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P<10(-7)) with SLE (PMID:15657875)
• IRF5 and IRF7 are critical mediators of TLR7 signaling (PMID:15695821)
• there are multiple IRF5 isoforms with distinct cell type-specific expression, localization, regulation, and function (PMID:15805103)
• a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity (PMID:16642019)
• Our results suggest that the IRF5 functional polymorphisms analyzed do not seem to be implicated in genetic susceptibility to rheumatoid arthritis. (PMID:17133578)
• results exclude the IRF5 rs2004640-T allele as a major genetic factor for rheumatoid arthritis in this French Caucasian population (PMID:17158136)
• results in an independent case-control sample confirm the robust association of the IRF5/rs2004640 T allele with SLE risk, and further support the relevance of the type I interferon system in the pathogenesis of SLE and autoimmunity (PMID:17166181)
• we show an association of systemic lupus erythematosus with 2 SNPs in the first intron; data support new mechanism by which an IRF5 polymorphism controls expression of alternate transcript variants which may have different effects on interferon signalling (PMID:17189288)
• the genetic effect on the risk of systemic lupus erythematosus mediated by IRF5 variants can be generally accepted in both white and Asian populations (PMID:17389033)
• A structural insertion/deletion in the IRF5 gene leads to expression of specific isoforms in the risk haplotype associated with system lupus erythematosus. (PMID:17393452)
• Assessment of three functional IRF5 alleles in patients with systemic lupus erythematosus illustrates how multiple common variants of the same gene can together influence the levels of risk of a common disease. (PMID:17412832)
• IRF5 could be involved in the more active disease and organ involvement known to occur among Mexican SLE patients. (PMID:17476532)
• functional IRF5 variations do not confer an obvious risk for type 1 diabetes (PMID:17557928)
• results help to understand the role of the IRF5 locus in SLE (systemic lupus erythematosus)susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms (PMID:17568788)
• Genetic variants of IRF5 contribute to a unique disease etiology and pathogenesis in rheumatoid arthritis patients/ (PMID:17599733)
• Epstein-Barr virus initially uses TLR7 signaling to enhance B-cell proliferation and subsequently modifies the pathway to regulate IRF-5 activity. (PMID:17609264)
• An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. (PMID:17881657)
• Primary Sjogren’s syndrome and systemic lupus erythematosus share IRF gene polymorphisms as a common genetic susceptibility factor. (PMID:18050197)
• IRF5 allele confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases (PMID:18063667)
• Polymorphisms at IRF5 did not associate with psoriasis per se; however, an interaction with class I major histocompatibility complex (MHC) genes was found. (PMID:18200047)
• a haplotype of IRF5 (interferon regulatory factor 5) gene has ssociation with systemic lupus erythematosus in Chinese (PMID:18260169)
• These findings add IRF5 to the short list of genes shown to be associated with multiple sclerosis in more than one population. (PMID:18285424)
• Genetic variants of IRF5 associate with systemic lupus erythematosus (SLE) in multiple populations, providing evidence that IRF5 is likely to be a crucial component in SLE pathogenesis among multiple ethnic groups. (PMID:18288123)
• IRF5 was found to be associated with systemic lupus erythematosus in Asian populations. Intron 1 single-nucleotide polymorphisms, rather than exon 6 and 3’-untranslated region polymorphisms, appeared to play a crucial role. (PMID:18311811)
• IRF5 mRNA is expressed in cells in atherosclerotic tissue and its expression is modified by single nucleotide polymorphisms in the IRF5 gene. (PMID:18323517)
• reveal the cell type-specific importance of IRF-5 in MyD88-mediated antiviral pathways and the widespread role of IRF-5 in the regulation of inflammatory cytokines (PMID:18332133)
• findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative. (PMID:18408250)
• IRF5 polymorphisms seem to influence RA susceptibility (PMID:18438842)
• epigenetic inactivation of the IFN pathway plays a critical role in cellular immortalization, and the reactivation of IFN-regulated genes by transcription factors IRF5 and/or IRF7 is sufficient to induce cellular senescence (PMID:18505922)
• The SNP rs7582694 in STAT4 displayed a increased risk of systemic lupus erythematosus with two independent risk alleles of the IRF5. (PMID:18579578)
• The IRF5 systemic lupus erythematosus (SLE) risk haplotype is associated with higher serum IFNalpha activity in SLE patients. (PMID:18668568)
• TT genotype of the rs2004640 dimorphism associated with rheumatoid arthritis in a Tunisian population (PMID:18752149)
• Data show that IRF-5, which is activated via the MyD88 pathway, is subjected to TRAF6-mediated K63-linked ubiquitination, which is important for IRF-5 nuclear translocation and target gene regulation. (PMID:18824541)
• genetic effects of IRF5 polymorphisms on the risk of systemic lupus erythematosus according to ethnicity (PMID:18843782)
• IRF5 polymorphism is associated with genetic susceptibility to rheumatoid arthritis at least in a Korean population (PMID:18843785)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	irf5	ENSDARG00000045681
mus_musculus	Irf5	ENSMUSG00000029771
rattus_norvegicus	Irf5	ENSRNOG00000007437

Paralogs (8): IRF6 (ENSG00000117595), IRF1 (ENSG00000125347), IRF3 (ENSG00000126456), IRF4 (ENSG00000137265), IRF8 (ENSG00000140968), IRF2 (ENSG00000168310), IRF7 (ENSG00000185507), IRF9 (ENSG00000213928)

Protein

Protein identifiers

Interferon regulatory factor 5 — Q13568 (reviewed: Q13568)

All UniProt accessions (6): Q13568, A0A0G2UM11, C9J7M2, C9JB67, C9JYP7, F8WDH6

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays a critical role in innate immunity by activating expression of type I interferon (IFN) IFNA and INFB and inflammatory cytokines downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9. Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters. Can efficiently activate both the IFN-beta (IFNB) and the IFN-alpha (IFNA) genes and mediate their induction downstream of the TLR-activated, MyD88-dependent pathway. Key transcription factor regulating the IFN response during SARS-CoV-2 infection.

Subunit / interactions. Homodimer, when phosphorylated. Interacts with TASL (via pLxIS motif); interaction takes place downstream of TLR7, TLR8 or TLR9, leading to its activation. Interacts with MYD88 and TRAF6.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylation of serine and threonine residues by IKBKB in a C-terminal autoinhibitory region, stimulates dimerization, transport into the nucleus, assembly with the coactivator CBP/EP300 and initiation of transcription. ‘Lys-63’-linked polyubiquitination by TRAF6 is required for activation.

Disease relevance. Inflammatory bowel disease 14 (IBD14) [MIM:612245] A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Disease susceptibility is associated with variants affecting the gene represented in this entry. Systemic lupus erythematosus 10 (SLEB10) [MIM:612251] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry. Rheumatoid arthritis (RA) [MIM:180300] An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Maintained as a monomer in an autoinhibited state. Phosphorylation and activation follow the following steps: innate adapter protein TASL recruits IRF5, thereby licensing IRF5 for phosphorylation by IKBKB. Phosphorylated IRF5 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce IFNs. (Microbial infection) Activated upon coronavirus SARS-CoV-2 infection.

Similarity. Belongs to the IRF family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q13568-1	1	yes
Q13568-2	2
Q13568-3	3
Q13568-4	4
Q13568-5	5
Q13568-6	6

RefSeq proteins (7): NP_001092097, NP_001092099, NP_001092100, NP_001229381, NP_001334857, NP_001351243, NP_116032 (=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 (46 total): strand 11, modified residue 9, helix 8, splice variant 6, cross-link 2, region of interest 2, short sequence motif 2, chain 1, DNA-binding region 1, mutagenesis site 1, sequence conflict 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3DSH	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13568-F1	73.89	0.41

Functional residue map

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

Post-translational modifications (11): 301, 431, 435, 437, 440, 446, 411, 412, 10, 158, 293

Mutagenesis-validated functional residues (1):

Position	Phenotype
446	abolished nuclear translocation.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-877300	Interferon gamma signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9860276	SLC15A4:TASL-dependent IRF5 activation
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-913531	Interferon Signaling

MSigDB gene sets: 491 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, MODULE_16, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (19): immune system process (GO:0002376), positive regulation of cytokine production involved in immune response (GO:0002720), regulation of transcription by RNA polymerase II (GO:0006357), inflammatory response (GO:0006954), cytokine-mediated signaling pathway (GO:0019221), positive regulation of type I interferon production (GO:0032481), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of interleukin-12 production (GO:0032735), positive regulation of apoptotic process (GO:0043065), innate immune response (GO:0045087), positive regulation of transcription by RNA polymerase II (GO:0045944), defense response to virus (GO:0051607), nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070431), cellular response to peptidoglycan (GO:0071224), cellular response to muramyl dipeptide (GO:0071225), cellular response to virus (GO:0098586), regulation of DNA-templated transcription (GO:0006355), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (12): 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 activator activity, RNA polymerase II-specific (GO:0001228), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), sequence-specific DNA binding (GO:0043565), protein serine/threonine kinase binding (GO:0120283), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), 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-7 pathways:

Category	Pathways
Interferon Signaling	2
Immune System	2
Toll-like Receptor Cascades	2
Toll Like Receptor 9 (TLR9) Cascade	1
Toll Like Receptor 7/8 (TLR7/8) Cascade	1
Innate 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
positive regulation of cytokine production	3
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
transcription by RNA polymerase II	2
defense response	2
positive regulation of type I interferon production	2
regulation of transcription by RNA polymerase II	2
response to virus	2
cellular response to nitrogen compound	2
cellular response to oxygen-containing compound	2
DNA-templated transcription	2
biological_process	1
cytokine production involved in immune response	1
positive regulation of production of molecular mediator of immune response	1
regulation of cytokine production involved in immune response	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
regulation of type I interferon production	1
type I interferon production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
immune response	1
defense response to symbiont	1
positive regulation of DNA-templated transcription	1
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1
response to peptidoglycan	1
cellular response to molecule of bacterial origin	1
response to muramyl dipeptide	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

2626 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRF5	MYD88	P78397	993
IRF5	TRAF6	Q9Y4K3	988
IRF5	STAT4	Q14765	860
IRF5	IRAK1	P51617	848
IRF5	TYK2	P29597	810
IRF5	PTPN22	Q9Y2R2	786
IRF5	TNFAIP3	P21580	785
IRF5	STAT1	P42224	781
IRF5	BANK1	Q8NDB2	754
IRF5	HLA-DRB1	P01911	750
IRF5	IL10	P22301	745
IRF5	IFIH1	Q9BYX4	743
IRF5	TLR8	Q9NR97	715
IRF5	TNIP1	Q15025	713
IRF5	IRF8	Q02556	711

IntAct

38 interactions, top by confidence:

A	B	Type	Score
RELA	IRF5	psi-mi:“MI:0915”(physical association)	0.660
IRF5	RELA	psi-mi:“MI:0915”(physical association)	0.660
IRF5	CREBBP	psi-mi:“MI:0407”(direct interaction)	0.620
IRF5	IRF5	psi-mi:“MI:0407”(direct interaction)	0.620
SGTA	IRF5	psi-mi:“MI:0915”(physical association)	0.540
IRF5	SGTA	psi-mi:“MI:0403”(colocalization)	0.540
IRF5	TRIM28	psi-mi:“MI:0915”(physical association)	0.520
IRF6	IRF8	psi-mi:“MI:0914”(association)	0.500
MAVS	IRF5	psi-mi:“MI:0915”(physical association)	0.500
SLC15A4	IRF5	psi-mi:“MI:0914”(association)	0.460
IRF5		psi-mi:“MI:0407”(direct interaction)	0.440
	IRF5	psi-mi:“MI:0407”(direct interaction)	0.440
IRF5	PPIB	psi-mi:“MI:0915”(physical association)	0.400
IRF5	SETDB1	psi-mi:“MI:0915”(physical association)	0.400
	IRF5	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (73): IRF5 (Affinity Capture-Western), IRF5 (Reconstituted Complex), IRF5 (Proximity Label-MS), BIRC3 (Affinity Capture-Western), IRF5 (Affinity Capture-Western), PELI1 (Affinity Capture-Western), COPS7A (Affinity Capture-MS), COPS4 (Affinity Capture-MS), COPS8 (Affinity Capture-Western), COPS6 (Affinity Capture-Western), GPS1 (Affinity Capture-Western), COPS2 (Affinity Capture-Western), COPS3 (Affinity Capture-Western), COPS4 (Affinity Capture-Western), COPS5 (Affinity Capture-Western)

ESM2 similar proteins: A2A8U2, A2RRU4, A2SXS5, A4D1U4, A6QM06, F1R7R1, G3X9C2, O00255, O75129, O75161, O88559, P40338, P59240, P97260, Q0P5I0, Q0VCT3, Q0VF94, Q12770, Q13568, Q17RQ9, Q32KQ7, Q3UTZ3, Q3ZCA1, Q4R4I0, Q50H33, Q5EBM0, Q5MNU5, Q5SNT2, Q69Z89, Q6GQT6, Q6L8S8, Q6L9W6, Q6ZVX7, Q6ZWB6, Q80U62, Q80Z10, Q8C0R7, Q8C190, Q8K2I9, Q8NFM7

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, P70434

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
RIPK2	up-regulates	IRF5	phosphorylation
TBK1	up-regulates	IRF5	phosphorylation
STAT5A	“up-regulates quantity by expression”	IRF5	“transcriptional regulation”
IRF5	“down-regulates quantity by repression”	IL10	“transcriptional regulation”
IRF4	“down-regulates activity”	IRF5
IRF5	up-regulates	M1_polarization
IRF5	up-regulates	IL1B	“transcriptional regulation”
IRF5	down-regulates	IL10	“transcriptional regulation”
IRF5	“up-regulates quantity by expression”	TNF	“transcriptional regulation”
LYN	“down-regulates activity”	IRF5	phosphorylation
CHUK	“down-regulates activity”	IRF5	phosphorylation
IKBKB	“up-regulates activity”	IRF5	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	53
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4526768	NM_001098629.3(IRF5):c.490C>T (p.Gln164Ter)	Likely pathogenic

SpliceAI

1528 predictions. Top by Δscore:

Variant	Effect	Δscore
7:128942274:AAGG:A	donor_loss	1.0000
7:128942275:AGGTA:A	donor_loss	1.0000
7:128942277:G:GC	donor_loss	1.0000
7:128942278:T:A	donor_loss	1.0000
7:128945842:CAGGC:C	acceptor_loss	1.0000
7:128945843:A:G	acceptor_loss	1.0000
7:128945843:AG:A	acceptor_gain	1.0000
7:128945844:GG:G	acceptor_gain	1.0000
7:128945844:GGC:G	acceptor_gain	1.0000
7:128945844:GGCCT:G	acceptor_gain	1.0000
7:128946491:T:A	acceptor_gain	1.0000
7:128946494:T:A	acceptor_gain	1.0000
7:128946497:GCAG:G	acceptor_loss	1.0000
7:128946498:CA:C	acceptor_loss	1.0000
7:128946499:A:AG	acceptor_gain	1.0000
7:128946500:G:GC	acceptor_gain	1.0000
7:128946500:GA:G	acceptor_gain	1.0000
7:128946500:GACT:G	acceptor_gain	1.0000
7:128946560:GAG:G	donor_gain	1.0000
7:128946561:AGGT:A	donor_loss	1.0000
7:128946562:GGTG:G	donor_loss	1.0000
7:128946563:G:GG	donor_gain	1.0000
7:128946564:T:G	donor_loss	1.0000
7:128946989:T:G	acceptor_gain	1.0000
7:128947531:GCCTC:G	donor_gain	1.0000
7:128947536:G:GG	donor_gain	1.0000
7:128947974:C:G	donor_gain	1.0000
7:128948202:T:TA	acceptor_gain	1.0000
7:128948208:A:AG	acceptor_gain	1.0000
7:128948209:G:GG	acceptor_gain	1.0000

AlphaMissense

3346 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:128942139:T:A	W20R	1.000
7:128942139:T:C	W20R	1.000
7:128942141:G:C	W20C	1.000
7:128942141:G:T	W20C	1.000
7:128942143:T:C	L21P	1.000
7:128942179:T:C	L33P	1.000
7:128942184:T:A	W35R	1.000
7:128942184:T:C	W35R	1.000
7:128942186:G:C	W35C	1.000
7:128942186:G:T	W35C	1.000
7:128942209:T:C	F43S	1.000
7:128942220:T:A	W47R	1.000
7:128942220:T:C	W47R	1.000
7:128942222:G:C	W47C	1.000
7:128942222:G:T	W47C	1.000
7:128942226:C:G	H49D	1.000
7:128942228:T:A	H49Q	1.000
7:128942228:T:G	H49Q	1.000
7:128942271:T:C	F64L	1.000
7:128942272:T:C	F64S	1.000
7:128942273:C:A	F64L	1.000
7:128942273:C:G	F64L	1.000
7:128945848:T:A	W67R	1.000
7:128945848:T:C	W67R	1.000
7:128945849:G:C	W67S	1.000
7:128945850:G:C	W67C	1.000
7:128945850:G:T	W67C	1.000
7:128945851:G:C	A68P	1.000
7:128945852:C:A	A68D	1.000
7:128945905:T:A	W86R	1.000

dbSNP variants (sampled 300 via entrez): RS1000047647 (7:128937927 A>G), RS1000140258 (7:128946222 A>G), RS1000250636 (7:128943811 C>T), RS1000482708 (7:128937609 G>A), RS1000692180 (7:128948973 C>G,T), RS1001064464 (7:128949322 A>G), RS1001184289 (7:128945480 A>G), RS1001249993 (7:128936675 C>T), RS1001465276 (7:128936325 A>G), RS1001797615 (7:128948492 CCT>C), RS1001816288 (7:128937628 C>G,T), RS1001911895 (7:128944335 C>A,T), RS1001965806 (7:128944068 T>G), RS1002766565 (7:128939488 T>C), RS1002796700 (7:128939353 C>A)

Disease associations

OMIM: gene MIM:607218 | disease phenotypes: MIM:612251, MIM:152700, MIM:601744, MIM:180300

GenCC curated gene-disease

Disease	Classification	Inheritance
systemic lupus erythematosus	Supportive	Unknown

Mondo (3): systemic lupus erythematosus, susceptibility to, 10 (MONDO:0012834), systemic lupus erythematosus (MONDO:0007915), rheumatoid arthritis (MONDO:0008383)

Orphanet (2): Systemic lupus erythematosus (Orphanet:536), NON RARE IN EUROPE: Rheumatoid arthritis (Orphanet:284130)

HPO phenotypes

112 total (30 of 112 shown, HPO-id order):

HPO	Term
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000155	Oral ulcer
HP:0000217	Xerostomia
HP:0000488	Retinopathy
HP:0000670	Carious teeth
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000820	Abnormality of the thyroid gland
HP:0000822	Hypertension
HP:0000939	Osteoporosis
HP:0000951	Abnormality of the skin
HP:0000952	Jaundice
HP:0000953	Hyperpigmentation of the skin
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0001000	Abnormality of skin pigmentation
HP:0001053	Hypopigmented skin patches
HP:0001114	Xanthelasma
HP:0001250	Seizure
HP:0001262	Excessive daytime somnolence
HP:0001278	Orthostatic hypotension
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001371	Flexion contracture
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001399	Hepatic failure
HP:0001402	Hepatocellular carcinoma
HP:0001409	Portal hypertension

GWAS associations

75 associations (top):

Study	Trait	p-value
GCST000142_6	Systemic lupus erythematosus	4.000000e-19
GCST000144_4	Systemic lupus erythematosus	2.000000e-11
GCST000507_9	Systemic lupus erythematosus	8.000000e-19
GCST000650_1	Systemic sclerosis	2.000000e-13
GCST000733_3	Primary biliary cholangitis	3.000000e-10
GCST000917_3	Rheumatoid arthritis	3.000000e-07
GCST000964_12	Ulcerative colitis	2.000000e-08
GCST000996_12	Systemic lupus erythematosus	6.000000e-09
GCST000996_3	Systemic lupus erythematosus	7.000000e-18
GCST001010_4	Primary biliary cholangitis	9.000000e-17
GCST001146_2	Systemic sclerosis	4.000000e-07
GCST001156_10	Systemic sclerosis	2.000000e-07
GCST001156_2	Systemic sclerosis	8.000000e-07
GCST001156_9	Systemic sclerosis	1.000000e-09
GCST001160_3	Systemic sclerosis	2.000000e-10
GCST001708_4	Systemic lupus erythematosus	4.000000e-08
GCST001728_11	Ulcerative colitis	4.000000e-14
GCST001795_18	Systemic lupus erythematosus	1.000000e-09
GCST002069_14	Systemic lupus erythematosus and Systemic sclerosis	1.000000e-29
GCST002318_154	Rheumatoid arthritis	1.000000e-14
GCST002318_155	Rheumatoid arthritis	4.000000e-12
GCST002463_16	Systemic lupus erythematosus	7.000000e-10
GCST003129_6	Primary biliary cholangitis	5.000000e-23
GCST003155_7	Systemic lupus erythematosus	9.000000e-110
GCST003156_22	Systemic lupus erythematosus	1.000000e-60
GCST003156_42	Systemic lupus erythematosus	1.000000e-48
GCST003252_26	Systemic lupus erythematosus	6.000000e-31
GCST003252_39	Systemic lupus erythematosus	1.000000e-23
GCST003599_9	Systemic lupus erythematosus	4.000000e-12
GCST003620_6	Systemic lupus erythematosus or rheumatoid arthritis	1.000000e-23

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004267	biliary liver cirrhosis
EFO:0008536	anti-centromere-antibody-positive systemic scleroderma
EFO:1001017	limited scleroderma
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001172	Arthritis, Rheumatoid	C05.550.114.154; C05.799.114; C17.300.775.099; C20.111.199
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	3
bisphenol F	affects cotreatment, increases expression	1
alpha phellandrene	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
nickel sulfate	increases expression	1
CGP 52608	affects binding, increases reaction	1
resiquimod	increases reaction, affects binding, decreases activity, decreases reaction	1
bardoxolone methyl	increases reaction, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
jinfukang	increases expression, affects cotreatment	1
Sorafenib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Allergens	affects cotreatment, increases expression	1
Amphotericin B	increases expression	1
Vehicle Emissions	increases expression, affects cotreatment	1
Cacodylic Acid	decreases expression	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Curcumin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Lipopolysaccharides	increases expression, increases reaction	1
Metformin	affects cotreatment, increases expression	1
Methotrexate	increases expression	1

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3G2	SEES3-1V human IRF5, clone1	Embryonic stem cell	Male
CVCL_A3G3	SEES3-1V human IRF5, clone2	Embryonic stem cell	Male
CVCL_A3G4	SEES3-1V human IRF5, clone3	Embryonic stem cell	Male
CVCL_D1WY	Abcam A-549 IRF5 KO	Cancer cell line	Male
CVCL_D2B9	Abcam HCT 116 IRF5 KO	Cancer cell line	Male
CVCL_E8F6	THP1-Dual KO-IRF5	Cancer cell line	Male
CVCL_SS97	HAP1 IRF5 (-) 1	Cancer cell line	Male
CVCL_SS98	HAP1 IRF5 (-) 2	Cancer cell line	Male
CVCL_SS99	HAP1 IRF5 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients