IRF8_HUMAN
ID IRF8_HUMAN Reviewed; 426 AA.
AC Q02556; A0AV82;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 15-JUL-1999, sequence version 2.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Interferon regulatory factor 8 {ECO:0000305};
DE Short=IRF-8;
DE AltName: Full=Interferon consensus sequence-binding protein {ECO:0000303|PubMed:1460054};
DE Short=H-ICSBP {ECO:0000303|PubMed:1460054};
DE Short=ICSBP {ECO:0000303|PubMed:1460054};
GN Name=IRF8 {ECO:0000303|PubMed:21524210, ECO:0000312|HGNC:HGNC:5358};
GN Synonyms=ICSBP1 {ECO:0000303|PubMed:1460054};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND INDUCTION BY IFNG.
RC TISSUE=Lung, and Monocyte;
RX PubMed=1460054; DOI=10.1016/s0021-9258(19)74081-2;
RA Weisz A., Marx P., Sharf R., Appella E., Driggers P.H., Ozato K.,
RA Levi B.-Z.;
RT "Human interferon consensus sequence binding protein is a negative
RT regulator of enhancer elements common to interferon-inducible genes.";
RL J. Biol. Chem. 267:25589-25596(1992).
RN [2]
RP SEQUENCE REVISION.
RA Schmidt M.;
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH COPS2.
RX PubMed=10991940; DOI=10.1074/jbc.m004900200;
RA Cohen H., Azriel A., Cohen T., Meraro D., Hashmueli S., Bech-Otschir D.,
RA Kraft R., Dubiel W., Levi B.Z.;
RT "Interaction between interferon consensus sequence-binding protein and
RT COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon
RT regulatory factor signaling and the COP9/signalosome.";
RL J. Biol. Chem. 275:39081-39089(2000).
RN [5]
RP INDUCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=23166356; DOI=10.1084/jem.20121387;
RA Basso K., Schneider C., Shen Q., Holmes A.B., Setty M., Leslie C.,
RA Dalla-Favera R.;
RT "BCL6 positively regulates AID and germinal center gene expression via
RT repression of miR-155.";
RL J. Exp. Med. 209:2455-2465(2012).
RN [6]
RP VARIANTS [LARGE SCALE ANALYSIS] LYS-81 AND THR-197.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [7]
RP VARIANT IMD32A ALA-80, VARIANT IMD32B GLU-108, CHARACTERIZATION OF VARIANT
RP IMD32A ALA-80, CHARACTERIZATION OF VARIANT IMD32B GLU-108, INVOLVEMENT IN
RP IMD32A, AND INVOLVEMENT IN IMD32B.
RX PubMed=21524210; DOI=10.1056/nejmoa1100066;
RA Hambleton S., Salem S., Bustamante J., Bigley V., Boisson-Dupuis S.,
RA Azevedo J., Fortin A., Haniffa M., Ceron-Gutierrez L., Bacon C.M.,
RA Menon G., Trouillet C., McDonald D., Carey P., Ginhoux F., Alsina L.,
RA Zumwalt T.J., Kong X.F., Kumararatne D., Butler K., Hubeau M., Feinberg J.,
RA Al-Muhsen S., Cant A., Abel L., Chaussabel D., Doffinger R., Talesnik E.,
RA Grumach A., Duarte A., Abarca K., Moraes-Vasconcelos D., Burk D.,
RA Berghuis A., Geissmann F., Collin M., Casanova J.L., Gros P.;
RT "IRF8 mutations and human dendritic-cell immunodeficiency.";
RL N. Engl. J. Med. 365:127-138(2011).
RN [8]
RP CHARACTERIZATION OF VARIANT IMD32B GLU-108, FUNCTION, SUBCELLULAR LOCATION,
RP UBIQUITINATION, DESUMOYLATION, AND MUTAGENESIS OF LYS-108.
RX PubMed=25122610; DOI=10.1182/blood-2014-04-570879;
RA Salem S., Langlais D., Lefebvre F., Bourque G., Bigley V., Haniffa M.,
RA Casanova J.L., Burk D., Berghuis A., Butler K.M., Leahy T.R., Hambleton S.,
RA Gros P.;
RT "Functional characterization of the human dendritic cell immunodeficiency
RT associated with the IRF8(K108E) mutation.";
RL Blood 124:1894-1904(2014).
RN [9]
RP FUNCTION.
RX PubMed=29434592; DOI=10.3389/fimmu.2018.00062;
RA Agod Z., Pazmandi K., Bencze D., Vereb G., Biro T., Szabo A.,
RA Rajnavolgyi E., Bacsi A., Engel P., Lanyi A.;
RT "Signaling lymphocyte activation molecule family 5 enhances autophagy and
RT fine-tunes cytokine response in monocyte-derived dendritic cells via
RT stabilization of interferon regulatory factor 8.";
RL Front. Immunol. 9:62-62(2018).
CC -!- FUNCTION: Transcription factor that specifically binds to the upstream
CC regulatory region of type I interferon (IFN) and IFN-inducible MHC
CC class I genes (the interferon consensus sequence (ICS))
CC (PubMed:25122610). Can both act as a transcriptional activator or
CC repressor (By similarity). Plays a negative regulatory role in cells of
CC the immune system (By similarity). Involved in CD8(+) dendritic cell
CC differentiation by forming a complex with the BATF-JUNB heterodimer in
CC immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-
CC 3'), an immune-specific regulatory element, followed by cooperative
CC binding of BATF and IRF8 and activation of genes (By similarity).
CC Required for the development of plasmacytoid dendritic cells (pDCs),
CC which produce most of the type I IFN in response to viral infection (By
CC similarity). Positively regulates macroautophagy in dendritic cells
CC (PubMed:29434592). {ECO:0000250|UniProtKB:P23611,
CC ECO:0000269|PubMed:25122610, ECO:0000269|PubMed:29434592}.
CC -!- SUBUNIT: Interacts (via C-terminus) with TRIM21 (via C-terminus).
CC Interacts with the BATF-JUNB heterodimer. Interacts with BATF (via bZIP
CC domain); the interaction is direct (By similarity). Interacts with
CC COPS2. {ECO:0000250, ECO:0000269|PubMed:10991940}.
CC -!- INTERACTION:
CC Q02556; O14896: IRF6; NbExp=3; IntAct=EBI-2866563, EBI-6115643;
CC Q02556; Q96CV9: OPTN; NbExp=3; IntAct=EBI-2866563, EBI-748974;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:23166356,
CC ECO:0000269|PubMed:25122610}. Cytoplasm {ECO:0000269|PubMed:25122610}.
CC Note=In resting macrophages, localizes in the cytoplasm. Translocated
CC in the nucleus upon IFN-gamma induction. {ECO:0000269|PubMed:25122610}.
CC -!- TISSUE SPECIFICITY: Predominantly expressed in lymphoid tissues.
CC {ECO:0000269|PubMed:1460054, ECO:0000269|PubMed:23166356}.
CC -!- INDUCTION: By IFNG/IFN-gamma. Negatively regulated by microRNA-155
CC (miR155). {ECO:0000269|PubMed:1460054, ECO:0000269|PubMed:23166356}.
CC -!- PTM: Ubiquitinated (PubMed:25122610). Ubiquitination by TRIM21 in
CC macrophages, a process that is strongly increased upon interferon gamma
CC stimulation, leds to the enhanced transcriptional activity of target
CC cytokine genes (By similarity). Ubiquitination leads to its degradation
CC by the proteasome (PubMed:25122610). {ECO:0000250,
CC ECO:0000269|PubMed:25122610}.
CC -!- PTM: Sumoylated with SUMO3. Desumoylated by SENP1.
CC {ECO:0000269|PubMed:25122610}.
CC -!- DISEASE: Immunodeficiency 32A (IMD32A) [MIM:614893]: An immunologic
CC disorder characterized by abnormal peripheral blood myeloid phenotype
CC with a marked loss of CD11C-positive/CD1C dendritic cells, resulting in
CC selective susceptibility to mycobacterial infections.
CC {ECO:0000269|PubMed:21524210}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Immunodeficiency 32B (IMD32B) [MIM:226990]: An autosomal
CC recessive primary immunodeficiency characterized by monocyte and
CC dendritic cell deficiency, myeloproliferation, and susceptibility to
CC severe opportunistic infections, including disseminated BCG infection
CC and oral candidiasis. {ECO:0000269|PubMed:21524210,
CC ECO:0000269|PubMed:25122610}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the IRF family. {ECO:0000255|PROSITE-
CC ProRule:PRU00840}.
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DR EMBL; M91196; AAB63813.1; -; mRNA.
DR EMBL; BC126247; AAI26248.1; -; mRNA.
DR CCDS; CCDS10956.1; -.
DR PIR; A45064; A45064.
DR RefSeq; NP_002154.1; NM_002163.2.
DR AlphaFoldDB; Q02556; -.
DR SMR; Q02556; -.
DR BioGRID; 109621; 54.
DR IntAct; Q02556; 41.
DR STRING; 9606.ENSP00000268638; -.
DR iPTMnet; Q02556; -.
DR PhosphoSitePlus; Q02556; -.
DR BioMuta; IRF8; -.
DR DMDM; 6016308; -.
DR jPOST; Q02556; -.
DR MassIVE; Q02556; -.
DR MaxQB; Q02556; -.
DR PaxDb; Q02556; -.
DR PeptideAtlas; Q02556; -.
DR PRIDE; Q02556; -.
DR ProteomicsDB; 58110; -.
DR Antibodypedia; 1058; 464 antibodies from 42 providers.
DR DNASU; 3394; -.
DR Ensembl; ENST00000268638.10; ENSP00000268638.4; ENSG00000140968.11.
DR GeneID; 3394; -.
DR KEGG; hsa:3394; -.
DR MANE-Select; ENST00000268638.10; ENSP00000268638.4; NM_002163.4; NP_002154.1.
DR UCSC; uc002fjh.4; human.
DR CTD; 3394; -.
DR DisGeNET; 3394; -.
DR GeneCards; IRF8; -.
DR HGNC; HGNC:5358; IRF8.
DR HPA; ENSG00000140968; Tissue enhanced (bone marrow, lymphoid tissue).
DR MalaCards; IRF8; -.
DR MIM; 226990; phenotype.
DR MIM; 601565; gene.
DR MIM; 614893; phenotype.
DR neXtProt; NX_Q02556; -.
DR OpenTargets; ENSG00000140968; -.
DR Orphanet; 319600; Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency.
DR PharmGKB; PA29606; -.
DR VEuPathDB; HostDB:ENSG00000140968; -.
DR eggNOG; ENOG502QT9P; Eukaryota.
DR GeneTree; ENSGT00940000158140; -.
DR InParanoid; Q02556; -.
DR OMA; EPSCVDE; -.
DR OrthoDB; 648909at2759; -.
DR PhylomeDB; Q02556; -.
DR TreeFam; TF328512; -.
DR PathwayCommons; Q02556; -.
DR Reactome; R-HSA-877300; Interferon gamma signaling.
DR Reactome; R-HSA-909733; Interferon alpha/beta signaling.
DR SignaLink; Q02556; -.
DR SIGNOR; Q02556; -.
DR BioGRID-ORCS; 3394; 40 hits in 1099 CRISPR screens.
DR ChiTaRS; IRF8; human.
DR GeneWiki; IRF8; -.
DR GenomeRNAi; 3394; -.
DR Pharos; Q02556; Tbio.
DR PRO; PR:Q02556; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q02556; protein.
DR Bgee; ENSG00000140968; Expressed in monocyte and 186 other tissues.
DR ExpressionAtlas; Q02556; baseline and differential.
DR Genevisible; Q02556; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IDA:UniProtKB.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl.
DR GO; GO:0042832; P:defense response to protozoan; IEA:Ensembl.
DR GO; GO:0097028; P:dendritic cell differentiation; ISS:UniProtKB.
DR GO; GO:0002316; P:follicular B cell differentiation; IEA:Ensembl.
DR GO; GO:0002314; P:germinal center B cell differentiation; IEA:Ensembl.
DR GO; GO:0006955; P:immune response; TAS:ProtInc.
DR GO; GO:0002376; P:immune system process; IBA:GO_Central.
DR GO; GO:0030099; P:myeloid cell differentiation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0006909; P:phagocytosis; IEA:Ensembl.
DR GO; GO:0002273; P:plasmacytoid dendritic cell differentiation; ISS:UniProtKB.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0032479; P:regulation of type I interferon production; ISS:UniProtKB.
DR CDD; cd00103; IRF; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 2.60.200.10; -; 1.
DR InterPro; IPR019817; Interferon_reg_fac_CS.
DR InterPro; IPR001346; Interferon_reg_fact_DNA-bd_dom.
DR InterPro; IPR019471; Interferon_reg_factor-3.
DR InterPro; IPR044400; IRF8.
DR InterPro; IPR017855; SMAD-like_dom_sf.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR PANTHER; PTHR11949:SF7; PTHR11949:SF7; 1.
DR Pfam; PF00605; IRF; 1.
DR Pfam; PF10401; IRF-3; 1.
DR PRINTS; PR00267; INTFRNREGFCT.
DR SMART; SM00348; IRF; 1.
DR SMART; SM01243; IRF-3; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR PROSITE; PS00601; IRF_1; 1.
DR PROSITE; PS51507; IRF_2; 1.
PE 1: Evidence at protein level;
KW Activator; Autophagy; Cytoplasm; Disease variant; DNA-binding; Nucleus;
KW Reference proteome; Repressor; Transcription; Transcription regulation;
KW Ubl conjugation.
FT CHAIN 1..426
FT /note="Interferon regulatory factor 8"
FT /id="PRO_0000154564"
FT DNA_BIND 7..114
FT /note="IRF tryptophan pentad repeat"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00840"
FT VARIANT 80
FT /note="T -> A (in IMD32A; impairs transcriptional activity
FT by disrupting the interaction between IRF8 and DNA;
FT dbSNP:rs397514711)"
FT /evidence="ECO:0000269|PubMed:21524210"
FT /id="VAR_070084"
FT VARIANT 81
FT /note="R -> K (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036490"
FT VARIANT 108
FT /note="K -> E (in IMD32B; in resting macrophages, no effect
FT on cytoplasmic subcellular localization; loss of nuclear
FT subcellular localization upon IFN-gamma induction;
FT decreased protein abundance; increased proteasome-dependent
FT degradation; increased ubiquitination and sumoylation; loss
FT of transcriptional repressor activity; loss of IRF1-
FT dependent transcriptional repressor activity; loss of IRF1-
FT dependent transcriptional activator activity; impairs
FT transcriptional activity by disrupting the interaction
FT between IRF8 and DNA; dbSNP:rs397514710)"
FT /evidence="ECO:0000269|PubMed:21524210,
FT ECO:0000269|PubMed:25122610"
FT /id="VAR_070085"
FT VARIANT 197
FT /note="A -> T (in a breast cancer sample; somatic mutation;
FT dbSNP:rs1372132995)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036491"
FT MUTAGEN 108
FT /note="K->H: In resting macrophages, no effect on
FT cytoplasmic subcellular localization. Decreased nuclear
FT subcellular localization upon IFN-gamma induction. Partial
FT loss of IRF1-dependent transcriptional activator activity."
FT /evidence="ECO:0000269|PubMed:25122610"
FT MUTAGEN 108
FT /note="K->Q: In resting macrophages, no effect on
FT cytoplasmic subcellular localization. Loss of nuclear
FT subcellular localization upon IFN-gamma induction. Loss of
FT IRF1-dependent transcriptional activator activity."
FT /evidence="ECO:0000269|PubMed:25122610"
FT MUTAGEN 108
FT /note="K->R: In resting macrophages, no effect on
FT cytoplasmic subcellular localization. No effect on nuclear
FT subcellular localization upon IFN-gamma induction. No
FT effect on transcriptional activator activity. No effect on
FT IRF1-dependent transcriptional activator activity."
FT /evidence="ECO:0000269|PubMed:25122610"
SQ SEQUENCE 426 AA; 48356 MW; 1535D1B7C83E0355 CRC64;
MCDRNGGRRL RQWLIEQIDS SMYPGLIWEN EEKSMFRIPW KHAGKQDYNQ EVDASIFKAW
AVFKGKFKEG DKAEPATWKT RLRCALNKSP DFEEVTDRSQ LDISEPYKVY RIVPEEEQKC
KLGVATAGCV NEVTEMECGR SEIDELIKEP SVDDYMGMIK RSPSPPEACR SQLLPDWWAQ
QPSTGVPLVT GYTTYDAHHS AFSQMVISFY YGGKLVGQAT TTCPEGCRLS LSQPGLPGTK
LYGPEGLELV RFPPADAIPS ERQRQVTRKL FGHLERGVLL HSSRQGVFVK RLCQGRVFCS
GNAVVCKGRP NKLERDEVVQ VFDTSQFFRE LQQFYNSQGR LPDGRVVLCF GEEFPDMAPL
RSKLILVQIE QLYVRQLAEE AGKSCGAGSV MQAPEEPPPD QVFRMFPDIC ASHQRSFFRE
NQQITV
