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P70671

- IRF3_MOUSE

UniProt

P70671 - IRF3_MOUSE

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Protein

Interferon regulatory factor 3

Gene

Irf3

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

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
Complete GO annotation...

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
Complete GO annotation...

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

BgeeiP70671.
CleanExiMM_IRF3.
ExpressionAtlasiP70671. baseline and differential.
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

        10         20         30         40         50
METPKPRILP WLVSQLDLGQ LEGVAWLDES RTRFRIPWKH GLRQDAQMAD
60 70 80 90 100
FGIFQAWAEA SGAYTPGKDK PDVSTWKRNF RSALNRKEVL RLAADNSKDP
110 120 130 140 150
YDPHKVYEFV TPGARDFVHL GASPDTNGKS SLPHSQENLP KLFDGLILGP
160 170 180 190 200
LKDEGSSDLA IVSDPSQQLP SPNVNNFLNP APQENPLKQL LAEEQWEFEV
210 220 230 240 250
TAFYRGRQVF QQTLFCPGGL RLVGSTADMT LPWQPVTLPD PEGFLTDKLV
260 270 280 290 300
KEYVGQVLKG LGNGLALWQA GQCLWAQRLG HSHAFWALGE ELLPDSGRGP
310 320 330 340 350
DGEVHKDKDG AVFDLRPFVA DLIAFMEGSG HSPRYTLWFC MGEMWPQDQP
360 370 380 390 400
WVKRLVMVKV VPTCLKELLE MAREGGASSL KTVDLHISNS QPISLTSDQY
410
KAYLQDLVED MDFQATGNI
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

Bgeei P70671.
CleanExi MM_IRF3.
ExpressionAtlasi P70671. baseline and differential.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 124 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