IRF3_PIG
ID IRF3_PIG Reviewed; 419 AA.
AC Q764M6;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 120.
DE RecName: Full=Interferon regulatory factor 3;
DE Short=IRF-3;
GN Name=IRF3;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=14681463; DOI=10.1093/nar/gkh037;
RA Uenishi H., Eguchi T., Suzuki K., Sawazaki T., Toki D., Shinkai H.,
RA Okumura N., Hamasima N., Awata T.;
RT "PEDE (Pig EST Data Explorer): construction of a database for ESTs derived
RT from porcine full-length cDNA libraries.";
RL Nucleic Acids Res. 32:D484-D488(2004).
RN [2]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH PORCINE EPIDEMIC DIARRHEA VIRUS
RP E PROTEIN (MICROBIAL INFECTION).
RX PubMed=33486326; DOI=10.1016/j.vetmic.2021.108994;
RA Zheng L., Wang X., Guo D., Cao J., Cheng L., Li X., Zou D., Zhang Y.,
RA Xu J., Wu X., Shen Y., Wang H., Yu W., Li L., Xiao L., Song B., Ma J.,
RA Liu X., Li P., Xu S., Xu X., Zhang H., Wu Z., Cao H.;
RT "Porcine epidemic diarrhea virus E protein suppresses RIG-I signaling-
RT mediated interferon-beta production.";
RL Vet. Microbiol. 254:108994-108994(2021).
RN [3]
RP INTERACTION WITH ASFV P14.5/E120R (MICROBIAL INFECTION).
RX PubMed=34190598; DOI=10.1128/jvi.00824-21;
RA Liu H., Zhu Z., Feng T., Ma Z., Xue Q., Wu P., Li P., Li S., Yang F.,
RA Cao W., Xue Z., Chen H., Liu X., Zheng H.;
RT "African swine fever virus E120R protein inhibits interferon-beta
RT production by interacting with IRF3 to block its activation.";
RL J. Virol. 95:E0082421-E0082421(2021).
RN [4]
RP INTERACTION WITH AFRICAN SWINE FEVER VIRUS PROTEIN MGF360-14L (MICROBIAL
RP INFECTION).
RX PubMed=35096660; DOI=10.3389/fcimb.2021.818969;
RA Wang Y., Cui S., Xin T., Wang X., Yu H., Chen S., Jiang Y., Gao X.,
RA Jiang Y., Guo X., Jia H., Zhu H.;
RT "African Swine Fever Virus MGF360-14L Negatively Regulates Type I
RT Interferon Signaling by Targeting IRF3.";
RL Front. Cell. Infect. Microbiol. 11:818969-818969(2021).
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 -!- SUBUNIT: (Microbial infection) Interacts with Porcine epidemic diarrhea
CC virus E protein; this interaction prevents IRF3 translocation to the
CC nucleus and thereby prevents type I interferon production.
CC {ECO:0000269|PubMed:33486326}.
CC -!- SUBUNIT: (Microbial infection) Interacts with African swine fever virus
CC (ASFV) P14.5/E120R; this interaction interfers with the recruitment of
CC IRF3 to TBK1, which in turn suppresses IRF3 phosphorylation, decreasing
CC interferon production via the cGAS/STING pathway.
CC {ECO:0000269|PubMed:34190598}.
CC -!- SUBUNIT: (Microbial infection) Interacts with African swine fever virus
CC (ASFV) MGF360-14L; this interaction mediates degradation of IRF3
CC through TRIM21 and ubiquitin-meditated proteolysis.
CC {ECO:0000269|PubMed:35096660}.
CC -!- INTERACTION:
CC Q764M6; F1RK46: CREBBP; NbExp=8; IntAct=EBI-12512266, EBI-12595681;
CC Q764M6; PRO_0000038050 [P19712]; Xeno; NbExp=4; IntAct=EBI-12512266, EBI-10901281;
CC Q764M6; Q68871; Xeno; NbExp=5; IntAct=EBI-12512266, EBI-12522528;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:33486326}. Nucleus
CC {ECO:0000269|PubMed:33486326}. 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; AB116563; BAD06317.1; -; mRNA.
DR RefSeq; NP_998935.1; NM_213770.1.
DR AlphaFoldDB; Q764M6; -.
DR SMR; Q764M6; -.
DR IntAct; Q764M6; 3.
DR STRING; 9823.ENSSSCP00000003447; -.
DR PaxDb; Q764M6; -.
DR PeptideAtlas; Q764M6; -.
DR PRIDE; Q764M6; -.
DR Ensembl; ENSSSCT00040019663; ENSSSCP00040008173; ENSSSCG00040014662.
DR GeneID; 396656; -.
DR KEGG; ssc:396656; -.
DR CTD; 3661; -.
DR eggNOG; ENOG502QTRR; Eukaryota.
DR InParanoid; Q764M6; -.
DR OrthoDB; 648909at2759; -.
DR Reactome; R-SSC-1169408; ISG15 antiviral mechanism.
DR Reactome; R-SSC-1606341; IRF3 mediated activation of type 1 IFN.
DR Reactome; R-SSC-168928; DDX58/IFIH1-mediated induction of interferon-alpha/beta.
DR Reactome; R-SSC-3134973; LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production.
DR Reactome; R-SSC-3134975; Regulation of innate immune responses to cytosolic DNA.
DR Reactome; R-SSC-3270619; IRF3-mediated induction of type I IFN.
DR Reactome; R-SSC-9013973; TICAM1-dependent activation of IRF3/IRF7.
DR Reactome; R-SSC-918233; TRAF3-dependent IRF activation pathway.
DR Reactome; R-SSC-933541; TRAF6 mediated IRF7 activation.
DR Reactome; R-SSC-936440; Negative regulators of DDX58/IFIH1 signaling.
DR Reactome; R-SSC-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
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:0045087; P:innate immune response; IEA:UniProtKB-KW.
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:0045893; P:positive regulation of transcription, DNA-templated; IEA:UniProt.
DR GO; GO:0032481; P:positive regulation of type I interferon production; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; ISS:UniProtKB.
DR CDD; cd00103; IRF; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 2.60.200.10; -; 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 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; PS00601; IRF_1; 1.
DR PROSITE; PS51507; IRF_2; 1.
PE 1: Evidence at protein level;
KW Activator; Antiviral defense; Cytoplasm; Disulfide bond; DNA-binding;
KW Host-virus interaction; Immunity; Innate immunity; Isopeptide bond;
KW Mitochondrion; Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..419
FT /note="Interferon regulatory factor 3"
FT /id="PRO_0000259485"
FT DNA_BIND 5..111
FT /note="IRF tryptophan pentad repeat"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00840"
FT REGION 118..137
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 140..419
FT /note="Mediates interaction with ZDHHC11"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT REGION 198..358
FT /note="Interaction with HERC5"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT SITE 121..122
FT /note="Cleavage; by CASP3"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT SITE 125..126
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 235
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 251
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 383
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 384
FT /note="Phosphoserine; by TBK1"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 394
FT /note="Phosphoserine; by IKKE"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 396
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT MOD_RES 402
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT DISULFID 265..287
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT CROSSLNK 191
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT CROSSLNK 358
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
FT CROSSLNK 364
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:Q14653"
SQ SEQUENCE 419 AA; 46646 MW; 8B731861BE002284 CRC64;
MGTQKPRILP WLISQLNQGQ LEGVAWLDEG HTRFRIPWKH GLRQDAQQED FGIFQAWAEA
SGAYTPGKDK PDLPTWKRNF RSALNRKEAL RLAEDHSKDP HDPHKIYEFV TSGVGDFPEP
DTSLDLSGRY STSDTHEDSL DKLLSGMDLA SDAGPQSLTL ALEQPPQLSL SPSVDAPASC
PNLGVRENPL KQLLANDDEW EFQVTVFYRG CQVFQQTVCS PGGLRLVGSE AEDGTLAGQP
VRLPDPAASL TDRGVADYVR RVLSCLGGGL ALWRAGQWLW AQRLGHCHVY WAMGEELIPD
SGHKPDGEVP KDREGGVFDL GPFIEDLIAF IEGSRRSPRY TLWFCMGQSW PQDEPWVKRL
VMVKVVPMCL RALVDMARDG GASSLENTVD LHISNSHPLS LTSDQYKACL RDLVEDMDF
