IRF3_BOVIN
ID IRF3_BOVIN Reviewed; 417 AA.
AC Q4JF28; A8W7A8; Q45VM9;
DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 02-AUG-2005, sequence version 1.
DT 03-AUG-2022, entry version 131.
DE RecName: Full=Interferon regulatory factor 3;
DE Short=IRF-3;
GN Name=IRF3;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Mammary gland;
RA Yang W., Seyfert H.M.;
RT "Dissection of MyD88 dependent and independent TLR-mediated signal
RT transduction in mammary epithelial cells of the cow.";
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Werling D.;
RT "Stimulation of the MyD88-independent pathway in bovine antigen presenting
RT cells.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Goodbourn S., Moganeradj K., McCauley J.;
RL Submitted (OCT-2007) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Crossbred X Angus; TISSUE=Ileum;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Key transcriptional regulator of type I interferon (IFN)-
CC dependent immune responses which plays a critical role in the innate
CC immune response against DNA and RNA viruses. Regulates the
CC transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-
CC stimulated genes (ISG) by binding to an interferon-stimulated response
CC element (ISRE) in their promoters. Acts as a more potent activator of
CC the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a
CC critical role in both the early and late phases of the IFNA/B gene
CC induction. Found in an inactive form in the cytoplasm of uninfected
CC cells and following viral infection, double-stranded RNA (dsRNA), or
CC toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1
CC kinases. This induces a conformational change, leading to its
CC dimerization and nuclear localization and association with CREB binding
CC protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex
CC which activates the transcription of the type I IFN and ISG genes. Can
CC activate distinct gene expression programs in macrophages and can
CC induce significant apoptosis in primary macrophages.
CC {ECO:0000250|UniProtKB:Q14653}.
CC -!- ACTIVITY REGULATION: In the absence of viral infection, maintained as a
CC monomer in an autoinhibited state. Phosphorylation by TBK1 and IKBKE
CC disrupts this autoinhibition leading to the liberation of the DNA-
CC binding and dimerization activities and its nuclear localization where
CC it can activate type I IFN and ISG genes. Phosphorylation and
CC activation follow the following steps: innate adapter protein MAVS,
CC STING1 or TICAM1 are first activated by viral RNA, cytosolic DNA and
CC bacterial lipopolysaccharide (LPS), respectively, leading to activation
CC of the kinases TBK1 and IKBKE. These kinases then phosphorylate the
CC adapter proteins on their pLxIS motif, leading to recruitment of IRF3,
CC thereby licensing IRF3 for phosphorylation by TBK1. Phosphorylated IRF3
CC dissociates from the adapter proteins, dimerizes, and then enters the
CC nucleus to induce IFNs. {ECO:0000250|UniProtKB:Q14653}.
CC -!- SUBUNIT: Monomer. Homodimer; phosphorylation-induced. Interacts (when
CC phosphorylated) with CREBBP. Interacts with MAVS (via phosphorylated
CC pLxIS motif). Interacts with TICAM1 (via phosphorylated pLxIS motif).
CC Interacts with STING1 (via phosphorylated pLxIS motif). Interacts with
CC IKBKE and TBK1. Interacts with TICAM2. Interacts with RBCK1. Interacts
CC with HERC5. Interacts with DDX3X; the interaction allows the
CC phosphorylation and activation of IRF3 by IKBKE. Interacts with TRIM21
CC and ULK1, in the presence of TRIM21; this interaction leads to IRF3
CC degradation by autophagy. Interacts with RIOK3; RIOK3 probably mediates
CC the interaction of TBK1 with IRF3. Interacts with ILRUN; the
CC interaction inhibits IRF3 binding to its DNA consensus sequence.
CC Interacts with LYAR; this interaction impairs IRF3 DNA-binding
CC activity. Interacts with TRAF3. Interacts with ZDHHC11; ZDHHC11
CC recruits IRF3 to STING1 upon DNA virus infection and thereby promotes
CC IRF3 activation (By similarity). Interacts with HSP90AA1; the
CC interaction mediates IRF3 association with TOMM70. Interacts with BCL2;
CC the interaction decreases upon Sendai virus infection. Interacts with
CC BAX; the interaction is direct, increases upon virus infection and
CC mediates the formation of the apoptosis complex
CC TOMM70:HSP90AA1:IRF3:BAX (By similarity).
CC {ECO:0000250|UniProtKB:Q14653}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q14653}. Nucleus
CC {ECO:0000250|UniProtKB:Q14653}. Mitochondrion
CC {ECO:0000250|UniProtKB:Q14653}. Note=Shuttles between cytoplasmic and
CC nuclear compartments, with export being the prevailing effect. When
CC activated, IRF3 interaction with CREBBP prevents its export to the
CC cytoplasm. Recruited to mitochondria via TOMM70:HSP90AA1 upon Sendai
CC virus infection. {ECO:0000250|UniProtKB:Q14653}.
CC -!- PTM: Constitutively phosphorylated on many Ser/Thr residues. Activated
CC following phosphorylation by TBK1 and IKBKE. Innate adapter protein
CC MAVS, STING1 or TICAM1 are first activated by viral RNA, cytosolic DNA,
CC and bacterial lipopolysaccharide (LPS), respectively, leading to
CC activation of the kinases TBK1 and IKBKE. These kinases then
CC phosphorylate the adapter proteins on the pLxIS motif, leading to
CC recruitment of IRF3, thereby licensing IRF3 for phosphorylation by
CC TBK1. Phosphorylated IRF3 dissociates from the adapter proteins,
CC dimerizes, and then enters the nucleus to induce IFNs.
CC {ECO:0000250|UniProtKB:Q14653}.
CC -!- PTM: Ubiquitinated; ubiquitination involves RBCK1 leading to
CC proteasomal degradation. Polyubiquitinated; ubiquitination involves
CC TRIM21 leading to proteasomal degradation. Ubiquitinated by UBE3C,
CC leading to its degradation. {ECO:0000250|UniProtKB:Q14653}.
CC -!- PTM: ISGylated by HERC5 resulting in sustained IRF3 activation and in
CC the inhibition of IRF3 ubiquitination by disrupting PIN1 binding. The
CC phosphorylation state of IRF3 does not alter ISGylation.
CC {ECO:0000250|UniProtKB:Q14653}.
CC -!- PTM: Proteolytically cleaved by apoptotic caspases during apoptosis,
CC leading to its inactivation. Cleavage by CASP3 during virus-induced
CC apoptosis inactivates it, preventing cytokine overproduction.
CC {ECO:0000250|UniProtKB:Q14653}.
CC -!- SIMILARITY: Belongs to the IRF family. {ECO:0000255|PROSITE-
CC ProRule:PRU00840}.
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DR EMBL; AJ879589; CAI53672.1; -; mRNA.
DR EMBL; DQ103889; AAZ38325.1; -; mRNA.
DR EMBL; EU194377; ABW74073.1; -; mRNA.
DR EMBL; BC102119; AAI02120.1; -; mRNA.
DR RefSeq; NP_001025016.1; NM_001029845.3.
DR AlphaFoldDB; Q4JF28; -.
DR SMR; Q4JF28; -.
DR IntAct; Q4JF28; 1.
DR STRING; 9913.ENSBTAP00000031815; -.
DR PaxDb; Q4JF28; -.
DR PRIDE; Q4JF28; -.
DR Ensembl; ENSBTAT00000031869; ENSBTAP00000031815; ENSBTAG00000006633.
DR GeneID; 516979; -.
DR KEGG; bta:516979; -.
DR CTD; 3661; -.
DR VEuPathDB; HostDB:ENSBTAG00000006633; -.
DR VGNC; VGNC:30274; IRF3.
DR eggNOG; ENOG502QTRR; Eukaryota.
DR GeneTree; ENSGT00940000160569; -.
DR HOGENOM; CLU_031544_2_0_1; -.
DR InParanoid; Q4JF28; -.
DR OMA; CHTYWAM; -.
DR OrthoDB; 648909at2759; -.
DR TreeFam; TF328512; -.
DR Reactome; R-BTA-1169408; ISG15 antiviral mechanism.
DR Reactome; R-BTA-1606341; IRF3 mediated activation of type 1 IFN.
DR Reactome; R-BTA-3270619; IRF3-mediated induction of type I IFN.
DR Reactome; R-BTA-9013973; TICAM1-dependent activation of IRF3/IRF7.
DR Reactome; R-BTA-918233; TRAF3-dependent IRF activation pathway.
DR Reactome; R-BTA-933541; TRAF6 mediated IRF7 activation.
DR Reactome; R-BTA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR Reactome; R-BTA-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.
DR Proteomes; UP000009136; Chromosome 18.
DR Bgee; ENSBTAG00000006633; Expressed in mesenteric lymph node and 104 other tissues.
DR ExpressionAtlas; Q4JF28; baseline and differential.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IEA:Ensembl.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IEA:Ensembl.
DR GO; GO:1990841; F:promoter-specific chromatin binding; IEA:Ensembl.
DR GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl.
DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0098586; P:cellular response to virus; ISS:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; ISS:UniProtKB.
DR GO; GO:0002376; P:immune system process; IBA:GO_Central.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0032727; P:positive regulation of interferon-alpha production; ISS:UniProtKB.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; ISS:UniProtKB.
DR GO; GO:0032481; P:positive regulation of type I interferon production; ISS:UniProtKB.
DR GO; GO:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0097300; P:programmed necrotic cell death; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IEA:Ensembl.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0060337; P:type I interferon signaling pathway; IEA:Ensembl.
DR CDD; cd00103; IRF; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 2.60.200.10; -; 1.
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 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; PS51507; IRF_2; 1.
PE 2: Evidence at transcript level;
KW Activator; Antiviral defense; Cytoplasm; Disulfide bond; DNA-binding;
KW Immunity; Innate immunity; Isopeptide bond; Mitochondrion; Nucleus;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..417
FT /note="Interferon regulatory factor 3"
FT /id="PRO_0000223675"
FT DNA_BIND 5..111
FT /note="IRF tryptophan pentad repeat"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00840"
FT REGION 111..134
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 140..417
FT /note="Mediates interaction with ZDHHC11"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT REGION 147..170
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 196..356
FT /note="Interaction with HERC5"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT COMPBIAS 150..167
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 121..122
FT /note="Cleavage; by CASP3"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 3
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 14
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 75
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 97
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 123
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P70671"
FT MOD_RES 184
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 249
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 381
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 382
FT /note="Phosphoserine; by TBK1"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 392
FT /note="Phosphoserine; by IKKE"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 394
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 400
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT DISULFID 263..285
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT CROSSLNK 189
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT CROSSLNK 356
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT CROSSLNK 362
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT CONFLICT 56..59
FT /note="AWAV -> VRAE (in Ref. 2; AAZ38325)"
FT /evidence="ECO:0000305"
FT CONFLICT 100..101
FT /note="SQ -> PH (in Ref. 2; AAZ38325)"
FT /evidence="ECO:0000305"
FT CONFLICT 115..117
FT /note="RDI -> GDF (in Ref. 2; AAZ38325)"
FT /evidence="ECO:0000305"
FT CONFLICT 130
FT /note="N -> S (in Ref. 2; AAZ38325)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 417 AA; 46646 MW; 06ADC5BCCD4D6389 CRC64;
MGTQKPRILP WLISQLDRGE LEGVAWLGES RTRFRIPWKH GLRQDAQQED FGIFQAWAVA
SGAYTPGKDK PDLPTWKRNF RSALNRKEVL RLAEDHSKDS QDPHKIYEFV NSGVRDIPEP
DTSQDNGRHN TSDTQEDTLE KLLSDMDLSP GGPSNLTMAS EKPPQFLQSP DSDIPALCPN
SGLSENPLKQ LLANEEDWEF EVTAFYRGCQ VFQQTVFCPG GLRLVGSEAG DRMLPGQPIR
LPDPATSLTD KSVTDYVQRV LSCLGGGLAL WRAGQWLCAQ RLGHCHVYWA IGEELLPSCG
HKPDGEVPKD REGGVFNLGP FITDLITFIE GSRRSPLYTL WFCVGQSWPQ DQPWIKRLVM
VKVVPMCLRV LVDIARQGGA SSLENTVDLH ISNSDPLSLT PDQYMACLQD LAEDMDF
