ID   IRF9_HUMAN              Reviewed;         393 AA.
AC   Q00978; D3DS61;
DT   01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT   01-APR-1993, sequence version 1.
DT   24-JAN-2024, entry version 193.
DE   RecName: Full=Interferon regulatory factor 9;
DE            Short=IRF-9;
DE   AltName: Full=IFN-alpha-responsive transcription factor subunit;
DE   AltName: Full=ISGF3 p48 subunit;
DE   AltName: Full=Interferon-stimulated gene factor 3 gamma;
DE            Short=ISGF-3 gamma;
DE   AltName: Full=Transcriptional regulator ISGF3 subunit gamma;
GN   Name=IRF9; Synonyms=ISGF3G;
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], AND PARTIAL PROTEIN SEQUENCE.
RX   PubMed=1630447; DOI=10.1128/mcb.12.8.3315-3324.1992;
RA   Veals S.A., Schindler C., Leonard D.G.B., Fu X.-Y., Aebersold R.H.,
RA   Darnell J.E. Jr., Levy D.E.;
RT   "Subunit of an alpha-interferon-responsive transcription factor is related
RT   to interferon regulatory factor and Myb families of DNA-binding proteins.";
RL   Mol. Cell. Biol. 12:3315-3324(1992).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Ovary;
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   SUBCELLULAR LOCATION.
RX   PubMed=11846981; DOI=10.1089/107999002753452719;
RA   Reich N.C.;
RT   "Nuclear/cytoplasmic localization of IRFs in response to viral infection or
RT   interferon stimulation.";
RL   J. Interferon Cytokine Res. 22:103-109(2002).
RN   [5]
RP   REVIEW.
RX   PubMed=10702714; DOI=10.1159/000053968;
RA   Cebulla C.M., Miller D.M., Sedmak D.D.;
RT   "Viral inhibition of interferon signal transduction.";
RL   Intervirology 42:325-330(1999).
RN   [6]
RP   FUNCTION, SUBCELLULAR LOCATION, INVOLVEMENT IN IMD65, VARIANTS HIS-127 AND
RP   CYS-292, CHARACTERIZATION OF VARIANTS HIS-127 AND CYS-292, AND MUTAGENESIS
RP   OF LYS-81 AND ARG-292.
RX   PubMed=30143481; DOI=10.1084/jem.20180628;
RA   Hernandez N., Melki I., Jing H., Habib T., Huang S.S.Y., Danielson J.,
RA   Kula T., Drutman S., Belkaya S., Rattina V., Lorenzo-Diaz L., Boulai A.,
RA   Rose Y., Kitabayashi N., Rodero M.P., Dumaine C., Blanche S., Lebras M.N.,
RA   Leung M.C., Mathew L.S., Boisson B., Zhang S.Y., Boisson-Dupuis S.,
RA   Giliani S., Chaussabel D., Notarangelo L.D., Elledge S.J.,
RA   Ciancanelli M.J., Abel L., Zhang Q., Marr N., Crow Y.J., Su H.C.,
RA   Casanova J.L.;
RT   "Life-threatening influenza pneumonitis in a child with inherited IRF9
RT   deficiency.";
RL   J. Exp. Med. 215:2567-2585(2018).
RN   [7]
RP   FUNCTION, AND INVOLVEMENT IN IMD65.
RX   PubMed=30826365; DOI=10.1016/j.jaci.2019.02.019;
RA   Bravo Garcia-Morato M., Calvo Apalategi A., Bravo-Gallego L.Y.,
RA   Blazquez Moreno A., Simon-Fuentes M., Garmendia J.V., Mendez Echevarria A.,
RA   Del Rosal Rabes T., Dominguez-Soto A., Lopez-Granados E., Reyburn H.T.,
RA   Rodriguez Pena R.;
RT   "Impaired control of multiple viral infections in a family with complete
RT   IRF9 deficiency.";
RL   J. Allergy Clin. Immunol. 144:309-312(2019).
RN   [8]
RP   UBIQUITINATION BY HERPES SIMPLEX VIRUS 2 PROTEIN ICP22 (MICROBIAL
RP   INFECTION).
RX   PubMed=32699158; DOI=10.4049/jimmunol.2000418;
RA   Zhang M., Fu M., Li M., Hu H., Gong S., Hu Q.;
RT   "Herpes Simplex Virus Type 2 Inhibits Type I IFN Signaling Mediated by the
RT   Novel E3 Ubiquitin Protein Ligase Activity of Viral Protein ICP22.";
RL   J. Immunol. 205:1281-1292(2020).
CC   -!- FUNCTION: Transcription factor that plays an essential role in anti-
CC       viral immunity. It mediates signaling by type I IFNs (IFN-alpha and
CC       IFN-beta). Following type I IFN binding to cell surface receptors, Jak
CC       kinases (TYK2 and JAK1) are activated, leading to tyrosine
CC       phosphorylation of STAT1 and STAT2. IRF9/ISGF3G associates with the
CC       phosphorylated STAT1:STAT2 dimer to form a complex termed ISGF3
CC       transcription factor, that enters the nucleus. ISGF3 binds to the IFN
CC       stimulated response element (ISRE) to activate the transcription of
CC       interferon stimulated genes, which drive the cell in an antiviral
CC       state. {ECO:0000269|PubMed:30143481}.
CC   -!- SUBUNIT: Interacts with STAT2 in the cytoplasm. Forms the interferon-
CC       stimulated gene factor 3 complex (ISGF3) with the heterodimer
CC       STAT1:STAT2; upon stimulation.
CC   -!- INTERACTION:
CC       Q00978; P48551: IFNAR2; NbExp=6; IntAct=EBI-626526, EBI-958408;
CC       Q00978; P52630: STAT2; NbExp=7; IntAct=EBI-626526, EBI-1546963;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11846981}. Nucleus
CC       {ECO:0000269|PubMed:11846981, ECO:0000269|PubMed:30143481}.
CC       Note=Translocated into the nucleus upon activation by IFN-alpha/beta.
CC   -!- INDUCTION: By IFN-alpha and IFNB1/IFN-beta.
CC   -!- PTM: (Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3
CC       ubiquitin ligase ICP22. {ECO:0000269|PubMed:32699158}.
CC   -!- DISEASE: Immunodeficiency 65 (IMD65) [MIM:618648]: An autosomal
CC       recessive immunologic disorder characterized by recurrent viral
CC       infections from early infancy. Clinical consequences are pneumonia,
CC       bronchiectasis, and septic shock. Affected individuals have lymphopenia
CC       or hypogammaglobulinemia, particularly during infection, and impaired
CC       cellular type I interferon response. Patients may have adverse response
CC       to vaccination with live attenuated vaccines.
CC       {ECO:0000269|PubMed:30143481, ECO:0000269|PubMed:30826365}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the IRF family. {ECO:0000255|PROSITE-
CC       ProRule:PRU00840}.
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DR   EMBL; M87503; AAA58687.1; -; mRNA.
DR   EMBL; CH471078; EAW66093.1; -; Genomic_DNA.
DR   EMBL; CH471078; EAW66094.1; -; Genomic_DNA.
DR   EMBL; BC035716; AAH35716.1; -; mRNA.
DR   CCDS; CCDS9615.1; -.
DR   PIR; A45017; A45017.
DR   RefSeq; NP_006075.3; NM_006084.4.
DR   AlphaFoldDB; Q00978; -.
DR   SMR; Q00978; -.
DR   BioGRID; 115652; 40.
DR   ComplexPortal; CPX-6016; ISGF3 complex.
DR   CORUM; Q00978; -.
DR   IntAct; Q00978; 25.
DR   MINT; Q00978; -.
DR   STRING; 9606.ENSP00000380073; -.
DR   iPTMnet; Q00978; -.
DR   PhosphoSitePlus; Q00978; -.
DR   BioMuta; IRF9; -.
DR   DMDM; 266392; -.
DR   EPD; Q00978; -.
DR   jPOST; Q00978; -.
DR   MassIVE; Q00978; -.
DR   MaxQB; Q00978; -.
DR   PaxDb; 9606-ENSP00000380073; -.
DR   PeptideAtlas; Q00978; -.
DR   ProteomicsDB; 57888; -.
DR   Pumba; Q00978; -.
DR   Antibodypedia; 663; 329 antibodies from 34 providers.
DR   DNASU; 10379; -.
DR   Ensembl; ENST00000396864.8; ENSP00000380073.3; ENSG00000213928.10.
DR   Ensembl; ENST00000646071.2; ENSP00000494792.1; ENSG00000285048.2.
DR   Ensembl; ENST00000699071.1; ENSP00000514112.1; ENSG00000213928.10.
DR   GeneID; 10379; -.
DR   KEGG; hsa:10379; -.
DR   MANE-Select; ENST00000396864.8; ENSP00000380073.3; NM_006084.5; NP_006075.3.
DR   UCSC; uc058zzb.1; human.
DR   AGR; HGNC:6131; -.
DR   CTD; 10379; -.
DR   DisGeNET; 10379; -.
DR   GeneCards; IRF9; -.
DR   HGNC; HGNC:6131; IRF9.
DR   HPA; ENSG00000213928; Low tissue specificity.
DR   MalaCards; IRF9; -.
DR   MIM; 147574; gene.
DR   MIM; 618648; phenotype.
DR   neXtProt; NX_Q00978; -.
DR   OpenTargets; ENSG00000213928; -.
DR   PharmGKB; PA162392259; -.
DR   VEuPathDB; HostDB:ENSG00000213928; -.
DR   eggNOG; ENOG502RR4E; Eukaryota.
DR   GeneTree; ENSGT00940000162115; -.
DR   HOGENOM; CLU_031544_1_2_1; -.
DR   InParanoid; Q00978; -.
DR   OMA; NFWEESC; -.
DR   OrthoDB; 3740806at2759; -.
DR   PhylomeDB; Q00978; -.
DR   TreeFam; TF328512; -.
DR   PathwayCommons; Q00978; -.
DR   Reactome; R-HSA-877300; Interferon gamma signaling.
DR   Reactome; R-HSA-909733; Interferon alpha/beta signaling.
DR   SignaLink; Q00978; -.
DR   SIGNOR; Q00978; -.
DR   BioGRID-ORCS; 10379; 24 hits in 1190 CRISPR screens.
DR   ChiTaRS; IRF9; human.
DR   GeneWiki; IRF9; -.
DR   GeneWiki; ISGF3G; -.
DR   GenomeRNAi; 10379; -.
DR   Pharos; Q00978; Tbio.
DR   PRO; PR:Q00978; -.
DR   Proteomes; UP000005640; Chromosome 14.
DR   RNAct; Q00978; Protein.
DR   Bgee; ENSG00000213928; Expressed in spleen and 99 other cell types or tissues.
DR   ExpressionAtlas; Q00978; baseline and differential.
DR   GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR   GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0070721; C:ISGF3 complex; IPI:ComplexPortal.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; TAS:ProtInc.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IMP:UniProtKB.
DR   GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR   GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
DR   GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
DR   GO; GO:0002376; P:immune system process; IBA:GO_Central.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ComplexPortal.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   GO; GO:0006366; P:transcription by RNA polymerase II; TAS:ProtInc.
DR   CDD; cd00103; IRF; 1.
DR   Gene3D; 2.60.200.10; -; 1.
DR   Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 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; 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; INTERFERON REGULATORY FACTOR; 1.
DR   PANTHER; PTHR11949:SF26; INTERFERON REGULATORY FACTOR 9; 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; SSF49879; SMAD/FHA domain; 1.
DR   SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1.
DR   PROSITE; PS00601; IRF_1; 1.
DR   PROSITE; PS51507; IRF_2; 1.
DR   Genevisible; Q00978; HS.
PE   1: Evidence at protein level;
KW   Activator; Antiviral defense; Cytoplasm; Direct protein sequencing;
KW   DNA-binding; Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW   Transcription regulation; Ubl conjugation.
FT   CHAIN           1..393
FT                   /note="Interferon regulatory factor 9"
FT                   /id="PRO_0000154567"
FT   DNA_BIND        9..116
FT                   /note="IRF tryptophan pentad repeat"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00840"
FT   REGION          120..151
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          163..202
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        135..149
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        176..202
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         139
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61179"
FT   VARIANT         127
FT                   /note="Q -> H (does not affect transcriptional activation
FT                   in response to type I interferon stimulation; does not
FT                   affect anti-viral immunity; dbSNP:rs145480303)"
FT                   /evidence="ECO:0000269|PubMed:30143481"
FT                   /id="VAR_083496"
FT   VARIANT         292
FT                   /note="R -> C (decreased transcriptional activation in
FT                   response to type I interferon stimulation;
FT                   dbSNP:rs1452927917)"
FT                   /evidence="ECO:0000269|PubMed:30143481"
FT                   /id="VAR_083497"
FT   MUTAGEN         81
FT                   /note="K->R: Loss of transcriptional activation in response
FT                   to type I interferon stimulation. Impaired anti-viral
FT                   immunity."
FT                   /evidence="ECO:0000269|PubMed:30143481"
FT   MUTAGEN         292
FT                   /note="R->Q: Decreased transcriptional activation in
FT                   response to type I interferon stimulation. Decreased
FT                   anti-viral immunity."
FT                   /evidence="ECO:0000269|PubMed:30143481"
SQ   SEQUENCE   393 AA;  43696 MW;  F8E3784354BFD4A9 CRC64;
     MASGRARCTR KLRNWVVEQV ESGQFPGVCW DDTAKTMFRI PWKHAGKQDF REDQDAAFFK
     AWAIFKGKYK EGDTGGPAVW KTRLRCALNK SSEFKEVPER GRMDVAEPYK VYQLLPPGIV
     SGQPGTQKVP SKRQHSSVSS ERKEEEDAMQ NCTLSPSVLQ DSLNNEEEGA SGGAVHSDIG
     SSSSSSSPEP QEVTDTTEAP FQGDQRSLEF LLPPEPDYSL LLTFIYNGRV VGEAQVQSLD
     CRLVAEPSGS ESSMEQVLFP KPGPLEPTQR LLSQLERGIL VASNPRGLFV QRLCPIPISW
     NAPQAPPGPG PHLLPSNECV ELFRTAYFCR DLVRYFQGLG PPPKFQVTLN FWEESHGSSH
     TPQNLITVKM EQAFARYLLE QTPEQQAAIL SLV
//