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P70671 (IRF3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 118. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Interferon regulatory factor 3

Short name=IRF-3
Gene names
Name:Irf3
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length419 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.3

Enzyme regulation

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.

Subunit structure

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.

Subcellular location

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.

Post-translational modification

Constitutively phosphorylated on many serines 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. An alternate model propose that the five serine/threonine residues between 388 and 397 are phosphorylated in response to a viral infection. Ref.8

Ubiquitinated; ubiquitination involves RBCK1 leading to proteasomal degradation. Polyubiquitinated; ubiquitination involves TRIM21 leading to proteasomal degradation 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.

Sequence similarities

Belongs to the IRF family.

Contains 1 IRF tryptophan pentad repeat DNA-binding domain.

Ontologies

Keywords
   Biological processAntiviral defense
Immunity
Innate immunity
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   LigandDNA-binding
   Molecular functionActivator
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular response to dsRNA

Inferred from electronic annotation. Source: Ensembl

defense response to virus

Inferred from mutant phenotype PubMed 23770239. Source: MGI

innate immune response

Inferred from electronic annotation. Source: UniProtKB-KW

lipopolysaccharide-mediated signaling pathway

Inferred from direct assay PubMed 12855817PubMed 12872135. Source: MGI

negative regulation of defense response to virus by host

Inferred from direct assay PubMed 18851954. Source: MGI

negative regulation of interferon-beta biosynthetic process

Inferred from direct assay PubMed 18851954. Source: MGI

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 18851954. Source: MGI

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of cytokine secretion

Inferred from electronic annotation. Source: Ensembl

positive regulation of interferon-alpha production

Inferred from mutant phenotype PubMed 18562536. Source: UniProtKB

positive regulation of interferon-beta production

Inferred from mutant phenotype PubMed 18562536. Source: UniProtKB

positive regulation of type I interferon-mediated signaling pathway

Inferred from mutant phenotype PubMed 17618271. Source: MGI

programmed necrotic cell death

Inferred from mutant phenotype PubMed 23770239. Source: MGI

response to bacterium

Inferred from direct assay PubMed 15661922. Source: MGI

response to exogenous dsRNA

Inferred from direct assay PubMed 12855817PubMed 12872135. Source: MGI

response to lipopolysaccharide

Inferred from direct assay PubMed 12855817PubMed 12872135. Source: MGI

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

type I interferon biosynthetic process

Inferred from genetic interaction Ref.3. Source: MGI

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 18851954. Source: MGI

cytosol

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 15661922PubMed 18851954. Source: MGI

   Molecular_functionprotein homodimerization activity

Inferred from direct assay PubMed 12855817PubMed 12872135PubMed 14556004. Source: MGI

regulatory region DNA binding

Inferred from electronic annotation. Source: InterPro

sequence-specific DNA binding transcription factor activity

Inferred from electronic annotation. Source: InterPro

transcription regulatory region DNA binding

Inferred from direct assay PubMed 18851954. Source: MGI

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 419419Interferon regulatory factor 3
PRO_0000154554

Regions

DNA binding5 – 111107IRF tryptophan pentad repeat

Amino acid modifications

Modified residue3881Phosphoserine; by IKKE By similarity
Cross-link188Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) By similarity
Cross-link353Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) By similarity
Cross-link359Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ISG15) By similarity

Sequences

Sequence LengthMass (Da)Tools
P70671 [UniParc].

Last modified February 1, 1997. Version 1.
Checksum: 1FF67C4E0FC7F027

FASTA41946,852
        10         20         30         40         50         60 
METPKPRILP WLVSQLDLGQ LEGVAWLDES RTRFRIPWKH GLRQDAQMAD FGIFQAWAEA 

        70         80         90        100        110        120 
SGAYTPGKDK PDVSTWKRNF RSALNRKEVL RLAADNSKDP YDPHKVYEFV TPGARDFVHL 

       130        140        150        160        170        180 
GASPDTNGKS SLPHSQENLP KLFDGLILGP LKDEGSSDLA IVSDPSQQLP SPNVNNFLNP 

       190        200        210        220        230        240 
APQENPLKQL LAEEQWEFEV TAFYRGRQVF QQTLFCPGGL RLVGSTADMT LPWQPVTLPD 

       250        260        270        280        290        300 
PEGFLTDKLV KEYVGQVLKG LGNGLALWQA GQCLWAQRLG HSHAFWALGE ELLPDSGRGP 

       310        320        330        340        350        360 
DGEVHKDKDG AVFDLRPFVA DLIAFMEGSG HSPRYTLWFC MGEMWPQDQP WVKRLVMVKV 

       370        380        390        400        410 
VPTCLKELLE MAREGGASSL KTVDLHISNS QPISLTSDQY KAYLQDLVED MDFQATGNI 

« Hide

References

« Hide 'large scale' references
[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]"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.
[8]"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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U75839 mRNA. Translation: AAB36924.1.
U75840 mRNA. Translation: AAB36925.1.
BC050882 mRNA. Translation: AAH50882.1.
RefSeqNP_058545.1. NM_016849.4.
XP_006541058.1. XM_006540995.1.
XP_006541059.1. XM_006540996.1.
UniGeneMm.3960.
Mm.489648.

3D structure databases

ProteinModelPortalP70671.
SMRP70671. Positions 4-110, 184-417.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid207570. 4 interactions.
DIPDIP-29881N.
IntActP70671. 2 interactions.
MINTMINT-2737174.
STRING10090.ENSMUSP00000103466.

PTM databases

PhosphoSiteP70671.

Proteomic databases

PaxDbP70671.
PRIDEP70671.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000003284; ENSMUSP00000003284; ENSMUSG00000003184.
ENSMUST00000107834; ENSMUSP00000103465; ENSMUSG00000003184.
ENSMUST00000107835; ENSMUSP00000103466; ENSMUSG00000003184.
GeneID54131.
KEGGmmu:54131.
UCSCuc009gsm.2. mouse.

Organism-specific databases

CTD3661.
MGIMGI:1859179. Irf3.

Phylogenomic databases

eggNOGNOG42868.
HOGENOMHOG000033705.
HOVERGENHBG105601.
InParanoidP70671.
KOK05411.
OMACHTYWAV.
OrthoDBEOG7CCBR1.
PhylomeDBP70671.
TreeFamTF328512.

Enzyme and pathway databases

ReactomeREACT_98458. Immune System.

Gene expression databases

ArrayExpressP70671.
BgeeP70671.
CleanExMM_IRF3.
GenevestigatorP70671.

Family and domain databases

Gene3D1.10.10.10. 1 hit.
2.60.200.10. 1 hit.
InterProIPR019817. 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]
PfamPF00605. IRF. 1 hit.
PF10401. IRF-3. 1 hit.
[Graphical view]
PRINTSPR00267. INTFRNREGFCT.
SMARTSM00348. IRF. 1 hit.
[Graphical view]
SUPFAMSSF49879. SSF49879. 1 hit.
PROSITEPS00601. IRF_1. 1 hit.
PS51507. IRF_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSIRF3. mouse.
NextBio310937.
PROP70671.
SOURCESearch...

Entry information

Entry nameIRF3_MOUSE
AccessionPrimary (citable) accession number: P70671
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: February 1, 1997
Last modified: April 16, 2014
This is version 118 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot