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P70671

- IRF3_MOUSE

UniProt

P70671 - IRF3_MOUSE

Protein

Interferon regulatory factor 3

Gene

Irf3

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 123 (01 Oct 2014)
      Sequence version 1 (01 Feb 1997)
      Previous versions | rss
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    Functioni

    Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses. 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. Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction. Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes. Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages.1 Publication

    Enzyme regulationi

    In the absence of viral infection, maintained as a monomer in an autoinhibited state and phosphorylation disrupts this autoinhibition leading to the liberation of the DNA-binding and dimerization activities and its nuclear localization where it can activate type I IFN and ISG genes.By similarity

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    DNA bindingi5 – 111107IRF tryptophan pentad repeatPROSITE-ProRule annotationAdd
    BLAST

    GO - Molecular functioni

    1. protein homodimerization activity Source: MGI
    2. sequence-specific DNA binding transcription factor activity Source: InterPro
    3. transcription regulatory region DNA binding Source: MGI

    GO - Biological processi

    1. cellular response to dsRNA Source: Ensembl
    2. defense response to virus Source: UniProtKB
    3. innate immune response Source: UniProtKB-KW
    4. lipopolysaccharide-mediated signaling pathway Source: MGI
    5. negative regulation of defense response to virus by host Source: MGI
    6. negative regulation of interferon-beta biosynthetic process Source: MGI
    7. negative regulation of transcription from RNA polymerase II promoter Source: MGI
    8. positive regulation of cytokine secretion Source: Ensembl
    9. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
    10. positive regulation of interferon-alpha production Source: UniProtKB
    11. positive regulation of interferon-beta production Source: UniProtKB
    12. positive regulation of type I interferon-mediated signaling pathway Source: MGI
    13. programmed necrotic cell death Source: MGI
    14. response to bacterium Source: MGI
    15. response to exogenous dsRNA Source: MGI
    16. response to lipopolysaccharide Source: MGI
    17. transcription, DNA-templated Source: UniProtKB-KW
    18. type I interferon biosynthetic process Source: MGI

    Keywords - Molecular functioni

    Activator

    Keywords - Biological processi

    Antiviral defense, Immunity, Innate immunity, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_196447. IRF3-mediated induction of type I IFN.
    REACT_196519. Regulation of innate immune responses to cytosolic DNA.
    REACT_198521. TRAF6 mediated IRF7 activation.
    REACT_198532. Negative regulators of RIG-I/MDA5 signaling.
    REACT_198533. ISG15 antiviral mechanism.
    REACT_198649. Factors involved in megakaryocyte development and platelet production.
    REACT_198660. Interferon gamma signaling.
    REACT_198980. IRF3 mediated activation of type 1 IFN.
    REACT_223626. LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production.
    REACT_225463. Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Interferon regulatory factor 3
    Short name:
    IRF-3
    Gene namesi
    Name:Irf3
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 7

    Organism-specific databases

    MGIiMGI:1859179. Irf3.

    Subcellular locationi

    Cytoplasm By similarity. Nucleus By similarity
    Note: Shuttles between cytoplasmic and nuclear compartments, with export being the prevailing effect. When activated, IRF3 interaction with CREBBP prevents its export to the cytoplasm By similarity.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: MGI
    2. cytosol Source: Reactome
    3. nucleus Source: MGI

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    Double knockout with TREX1 does not show a visible phenotype.1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 419419Interferon regulatory factor 3PRO_0000154554Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei3 – 31PhosphothreonineBy similarity
    Modified residuei14 – 141PhosphoserineBy similarity
    Modified residuei75 – 751PhosphothreonineBy similarity
    Modified residuei97 – 971PhosphoserineBy similarity
    Cross-linki188 – 188Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15)By similarity
    Modified residuei230 – 2301PhosphothreonineBy similarity
    Modified residuei237 – 2371PhosphothreonineBy similarity
    Modified residuei246 – 2461PhosphothreonineBy similarity
    Cross-linki353 – 353Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15)By similarity
    Cross-linki359 – 359Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15)By similarity
    Modified residuei379 – 3791Phosphoserine; by TBK1By similarity
    Modified residuei388 – 3881Phosphoserine; by IKKEBy similarity
    Modified residuei390 – 3901PhosphoserineBy similarity
    Modified residuei396 – 3961PhosphothreonineBy similarity

    Post-translational modificationi

    Constitutively phosphorylated on many Ser/Thr residues. C-terminal serine/threonine cluster is phosphorylated in response of induction by IKBKE and TBK1. Phosphorylated at Ser-388 by IKBKE upon ssRNA viral infection. Ser-378 and Ser-379 may be specifically phosphorylated in response to induction. Phosphorylation at Ser-379 by TBK1 results in oligomerization. An alternate model propose that the five serine/threonine residues between 388 and 397 are phosphorylated in response to a viral infection.1 Publication
    Ubiquitinated; ubiquitination involves RBCK1 leading to proteasomal degradation. Polyubiquitinated; ubiquitination involves TRIM21 leading to proteasomal degradation By similarity.By similarity
    ISGylated resulting in sustained IRF3 activation and in the inhibition of IRF3 ubiquitination by disrupting PIN1 binding. The phosphorylation state of IRF3 does not alter ISGylation By similarity.By similarity

    Keywords - PTMi

    Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiP70671.
    PaxDbiP70671.
    PRIDEiP70671.

    PTM databases

    PhosphoSiteiP70671.

    Expressioni

    Gene expression databases

    ArrayExpressiP70671.
    BgeeiP70671.
    CleanExiMM_IRF3.
    GenevestigatoriP70671.

    Interactioni

    Subunit structurei

    Monomer. Homodimer; phosphorylation-induced. Heterodimer with IRF7. Interacts with CREBBP. May interact with MAVS. Interacts with IKBKE and TBK1. Interacts with TICAM1 and TICAM2. Interacts with rotavirus A NSP1 (via C-terminus); this interaction leads to the proteasome-dependent degradation of IRF3. Interacts with RBCK1. Interacts with TRIM21. Interacts with HERC5. InteractS with DDX3X; the interaction allows the phosphorylation and activation of IRF3 by IKBKE.

    Protein-protein interaction databases

    BioGridi207570. 4 interactions.
    DIPiDIP-29881N.
    IntActiP70671. 2 interactions.
    MINTiMINT-2737174.
    STRINGi10090.ENSMUSP00000103466.

    Structurei

    3D structure databases

    ProteinModelPortaliP70671.
    SMRiP70671. Positions 4-110, 184-417.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the IRF family.PROSITE-ProRule annotation
    Contains 1 IRF tryptophan pentad repeat DNA-binding domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiNOG42868.
    HOGENOMiHOG000033705.
    HOVERGENiHBG105601.
    InParanoidiP70671.
    KOiK05411.
    OMAiCHTYWAV.
    OrthoDBiEOG7CCBR1.
    PhylomeDBiP70671.
    TreeFamiTF328512.

    Family and domain databases

    Gene3Di1.10.10.10. 1 hit.
    2.60.200.10. 1 hit.
    InterProiIPR019817. Interferon_reg_fac_CS.
    IPR001346. Interferon_reg_fact_DNA-bd_dom.
    IPR019471. Interferon_reg_factor-3.
    IPR017855. SMAD_dom-like.
    IPR008984. SMAD_FHA_domain.
    IPR011991. WHTH_DNA-bd_dom.
    [Graphical view]
    PfamiPF00605. IRF. 1 hit.
    PF10401. IRF-3. 1 hit.
    [Graphical view]
    PRINTSiPR00267. INTFRNREGFCT.
    SMARTiSM00348. IRF. 1 hit.
    [Graphical view]
    SUPFAMiSSF49879. SSF49879. 1 hit.
    PROSITEiPS00601. IRF_1. 1 hit.
    PS51507. IRF_2. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P70671-1 [UniParc]FASTAAdd to Basket

    « Hide

    METPKPRILP WLVSQLDLGQ LEGVAWLDES RTRFRIPWKH GLRQDAQMAD    50
    FGIFQAWAEA SGAYTPGKDK PDVSTWKRNF RSALNRKEVL RLAADNSKDP 100
    YDPHKVYEFV TPGARDFVHL GASPDTNGKS SLPHSQENLP KLFDGLILGP 150
    LKDEGSSDLA IVSDPSQQLP SPNVNNFLNP APQENPLKQL LAEEQWEFEV 200
    TAFYRGRQVF QQTLFCPGGL RLVGSTADMT LPWQPVTLPD PEGFLTDKLV 250
    KEYVGQVLKG LGNGLALWQA GQCLWAQRLG HSHAFWALGE ELLPDSGRGP 300
    DGEVHKDKDG AVFDLRPFVA DLIAFMEGSG HSPRYTLWFC MGEMWPQDQP 350
    WVKRLVMVKV VPTCLKELLE MAREGGASSL KTVDLHISNS QPISLTSDQY 400
    KAYLQDLVED MDFQATGNI 419
    Length:419
    Mass (Da):46,852
    Last modified:February 1, 1997 - v1
    Checksum:i1FF67C4E0FC7F027
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U75839 mRNA. Translation: AAB36924.1.
    U75840 mRNA. Translation: AAB36925.1.
    BC050882 mRNA. Translation: AAH50882.1.
    CCDSiCCDS21224.1.
    RefSeqiNP_058545.1. NM_016849.4.
    XP_006541058.1. XM_006540995.1.
    XP_006541059.1. XM_006540996.1.
    UniGeneiMm.3960.
    Mm.489648.

    Genome annotation databases

    EnsembliENSMUST00000003284; ENSMUSP00000003284; ENSMUSG00000003184.
    ENSMUST00000107834; ENSMUSP00000103465; ENSMUSG00000003184.
    ENSMUST00000107835; ENSMUSP00000103466; ENSMUSG00000003184.
    GeneIDi54131.
    KEGGimmu:54131.
    UCSCiuc009gsm.2. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U75839 mRNA. Translation: AAB36924.1 .
    U75840 mRNA. Translation: AAB36925.1 .
    BC050882 mRNA. Translation: AAH50882.1 .
    CCDSi CCDS21224.1.
    RefSeqi NP_058545.1. NM_016849.4.
    XP_006541058.1. XM_006540995.1.
    XP_006541059.1. XM_006540996.1.
    UniGenei Mm.3960.
    Mm.489648.

    3D structure databases

    ProteinModelPortali P70671.
    SMRi P70671. Positions 4-110, 184-417.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 207570. 4 interactions.
    DIPi DIP-29881N.
    IntActi P70671. 2 interactions.
    MINTi MINT-2737174.
    STRINGi 10090.ENSMUSP00000103466.

    PTM databases

    PhosphoSitei P70671.

    Proteomic databases

    MaxQBi P70671.
    PaxDbi P70671.
    PRIDEi P70671.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000003284 ; ENSMUSP00000003284 ; ENSMUSG00000003184 .
    ENSMUST00000107834 ; ENSMUSP00000103465 ; ENSMUSG00000003184 .
    ENSMUST00000107835 ; ENSMUSP00000103466 ; ENSMUSG00000003184 .
    GeneIDi 54131.
    KEGGi mmu:54131.
    UCSCi uc009gsm.2. mouse.

    Organism-specific databases

    CTDi 3661.
    MGIi MGI:1859179. Irf3.

    Phylogenomic databases

    eggNOGi NOG42868.
    HOGENOMi HOG000033705.
    HOVERGENi HBG105601.
    InParanoidi P70671.
    KOi K05411.
    OMAi CHTYWAV.
    OrthoDBi EOG7CCBR1.
    PhylomeDBi P70671.
    TreeFami TF328512.

    Enzyme and pathway databases

    Reactomei REACT_196447. IRF3-mediated induction of type I IFN.
    REACT_196519. Regulation of innate immune responses to cytosolic DNA.
    REACT_198521. TRAF6 mediated IRF7 activation.
    REACT_198532. Negative regulators of RIG-I/MDA5 signaling.
    REACT_198533. ISG15 antiviral mechanism.
    REACT_198649. Factors involved in megakaryocyte development and platelet production.
    REACT_198660. Interferon gamma signaling.
    REACT_198980. IRF3 mediated activation of type 1 IFN.
    REACT_223626. LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production.
    REACT_225463. Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.

    Miscellaneous databases

    ChiTaRSi IRF3. mouse.
    NextBioi 310937.
    PROi P70671.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P70671.
    Bgeei P70671.
    CleanExi MM_IRF3.
    Genevestigatori P70671.

    Family and domain databases

    Gene3Di 1.10.10.10. 1 hit.
    2.60.200.10. 1 hit.
    InterProi IPR019817. Interferon_reg_fac_CS.
    IPR001346. Interferon_reg_fact_DNA-bd_dom.
    IPR019471. Interferon_reg_factor-3.
    IPR017855. SMAD_dom-like.
    IPR008984. SMAD_FHA_domain.
    IPR011991. WHTH_DNA-bd_dom.
    [Graphical view ]
    Pfami PF00605. IRF. 1 hit.
    PF10401. IRF-3. 1 hit.
    [Graphical view ]
    PRINTSi PR00267. INTFRNREGFCT.
    SMARTi SM00348. IRF. 1 hit.
    [Graphical view ]
    SUPFAMi SSF49879. SSF49879. 1 hit.
    PROSITEi PS00601. IRF_1. 1 hit.
    PS51507. IRF_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. Hakem R., Grossman A., Antonio L., Suggs S., Mak T.W.
      Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Strain: BALB/c.
      Tissue: Liver.
    2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Strain: C57BL/6.
      Tissue: Brain.
    3. "IRF-7 is the master regulator of type-I interferon-dependent immune responses."
      Honda K., Yanai H., Negishi H., Asagiri M., Sato M., Mizutani T., Shimada N., Ohba Y., Takaoka A., Yoshida N., Taniguchi T.
      Nature 434:772-777(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    4. "Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages."
      Solis M., Goubau D., Romieu-Mourez R., Genin P., Civas A., Hiscott J.
      Biochem. Pharmacol. 72:1469-1476(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    5. "Type I interferon gene induction by the interferon regulatory factor family of transcription factors."
      Honda K., Takaoka A., Taniguchi T.
      Immunity 25:349-360(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    6. Erratum
      Honda K., Takaoka A., Taniguchi T.
      Immunity 25:849-849(2006)
    7. "Trex1 prevents cell-intrinsic initiation of autoimmunity."
      Stetson D.B., Ko J.S., Heidmann T., Medzhitov R.
      Cell 134:587-598(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    8. "Regulation of immunity and oncogenesis by the IRF transcription factor family."
      Savitsky D., Tamura T., Yanai H., Taniguchi T.
      Cancer Immunol. Immunother. 59:489-510(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON FUNCTION.
    9. "Inhibitor of kappaB kinase epsilon (IKK(epsilon)), STAT1, and IFIT2 proteins define novel innate immune effector pathway against West Nile virus infection."
      Perwitasari O., Cho H., Diamond M.S., Gale M. Jr.
      J. Biol. Chem. 286:44412-44423(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION UPON SSRNA VIRAL INFECTION.

    Entry informationi

    Entry nameiIRF3_MOUSE
    AccessioniPrimary (citable) accession number: P70671
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 1, 1997
    Last sequence update: February 1, 1997
    Last modified: October 1, 2014
    This is version 123 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3