ID   IRF3_HUMAN              Reviewed;         427 AA.
AC   Q14653; A8K7L2; B2RAZ3; Q5FBY1; Q5FBY2; Q5FBY4; Q7Z5G6;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1997, sequence version 1.
DT   29-MAY-2024, entry version 218.
DE   RecName: Full=Interferon regulatory factor 3 {ECO:0000303|PubMed:9566918, ECO:0000303|PubMed:9803267};
DE            Short=IRF-3 {ECO:0000303|PubMed:9566918};
GN   Name=IRF3 {ECO:0000303|PubMed:9803267, ECO:0000312|HGNC:HGNC:6118};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RC   TISSUE=Retina;
RX   PubMed=8524823; DOI=10.1073/pnas.92.25.11657;
RA   Au W.W.-C., Moore P.P.A., Lowther W.W., Juang Y.-T., Pitha P.M.;
RT   "Identification of a member of the interferon regulatory factor family that
RT   binds to the interferon-stimulated response element and activates
RT   expression of interferon-induced genes.";
RL   Proc. Natl. Acad. Sci. U.S.A. 92:11657-11661(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3 AND 5).
RA   Tabata Y., Sameshima E., Hayashi A., Iida K., Mitsuyama M., Kanai S.,
RA   Furuya T., Saito T.;
RT   "IRF3 mRNA, nirs splice variants.";
RL   Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT THR-427.
RC   TISSUE=Spleen;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057824; DOI=10.1038/nature02399;
RA   Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA   Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA   Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA   Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA   Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA   Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA   Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA   Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA   Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA   McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA   Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA   Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA   She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA   Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA   Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA   Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA   Rubin E.M., Lucas S.M.;
RT   "The DNA sequence and biology of human chromosome 19.";
RL   Nature 428:529-535(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT THR-427.
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
RC   TISSUE=Eye, and Kidney;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 323-413.
RX   PubMed=9803267; DOI=10.1046/j.1469-1809.1998.6230231.x;
RA   Bellingham J., Gregory-Evans K., Gregory-Evans C.Y.;
RT   "Mapping of human interferon regulatory factor 3 (IRF3) to chromosome
RT   19q13.3-13.4 by an intragenic polymorphic marker.";
RL   Ann. Hum. Genet. 62:231-234(1998).
RN   [8]
RP   MUTAGENESIS OF 385-SER-SER-386 AND 396-SER--SER-405.
RX   PubMed=9566918; DOI=10.1128/mcb.18.5.2986;
RA   Lin R., Heylbroeck C., Pitha P.M., Hiscott J.;
RT   "Virus-dependent phosphorylation of the IRF-3 transcription factor
RT   regulates nuclear translocation, transactivation potential, and proteasome-
RT   mediated degradation.";
RL   Mol. Cell. Biol. 18:2986-2996(1998).
RN   [9]
RP   MUTAGENESIS OF SER-385 AND SER-386.
RX   PubMed=10920266; DOI=10.1093/oxfordjournals.jbchem.a022753;
RA   Suhara W., Yoneyama M., Iwamura T., Yoshimura S., Tamura K., Namiki H.,
RA   Aimoto S., Fujita T.;
RT   "Analyses of virus-induced homomeric and heteromeric protein associations
RT   between IRF-3 and coactivator CBP/p300.";
RL   J. Biochem. 128:301-307(2000).
RN   [10]
RP   SUBCELLULAR LOCATION, AND MUTAGENESIS OF 77-LYS-ARG-78; 86-ARG-LYS-87 AND
RP   139-ILE-LEU-140.
RX   PubMed=10805757; DOI=10.1128/mcb.20.11.4159-4168.2000;
RA   Kumar K.P., McBride K.M., Weaver B.K., Dingwall C., Reich N.C.;
RT   "Regulated nuclear-cytoplasmic localization of interferon regulatory factor
RT   3, a subunit of double-stranded RNA-activated factor 1.";
RL   Mol. Cell. Biol. 20:4159-4168(2000).
RN   [11]
RP   PHOSPHORYLATION.
RX   PubMed=11035028; DOI=10.1074/jbc.m007790200;
RA   Servant M.J., ten Oever B., LePage C., Conti L., Gessani S., Julkunen I.,
RA   Lin R., Hiscott J.;
RT   "Identification of distinct signaling pathways leading to the
RT   phosphorylation of interferon regulatory factor 3.";
RL   J. Biol. Chem. 276:355-363(2001).
RN   [12]
RP   INHIBITION OF PHOSPHORYLATION BY VACCINIA VIRUS PROTEIN E3 (MICROBIAL
RP   INFECTION).
RX   PubMed=11124948; DOI=10.1074/jbc.m008717200;
RA   Smith E.J., Marie I.J., Prakash A., Garcia-Sastre A., Levy D.E.;
RT   "IRF3 and IRF7 phosphorylation in virus-infected cells does not require
RT   double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is
RT   blocked by Vaccinia virus E3L protein.";
RL   J. Biol. Chem. 276:8951-8957(2001).
RN   [13]
RP   INTERACTION WITH HHV-8 PROTEIN VIRF1 (MICROBIAL INFECTION).
RX   PubMed=11314014; DOI=10.1038/sj.onc.1204163;
RA   Lin R., Genin P., Mamane Y., Sgarbanti M., Battistini A.,
RA   Harrington W.J. Jr., Barber G.N., Hiscott J.;
RT   "HHV-8 encoded vIRF-1 represses the interferon antiviral response by
RT   blocking IRF-3 recruitment of the CBP/p300 coactivators.";
RL   Oncogene 20:800-811(2001).
RN   [14]
RP   REVIEW.
RX   PubMed=11846977; DOI=10.1089/107999002753452674;
RA   Yoneyama M., Suhara W., Fujita T.;
RT   "Control of IRF-3 activation by phosphorylation.";
RL   J. Interferon Cytokine Res. 22:73-76(2002).
RN   [15]
RP   INTERACTION WITH TICAM1.
RX   PubMed=12471095; DOI=10.4049/jimmunol.169.12.6668;
RA   Yamamoto M., Sato S., Mori K., Hoshino K., Takeuchi O., Takeda K.,
RA   Akira S.;
RT   "A novel Toll/IL-1 receptor domain-containing adapter that preferentially
RT   activates the IFN-beta promoter in the Toll-like receptor signaling.";
RL   J. Immunol. 169:6668-6672(2002).
RN   [16]
RP   INTERACTION WITH ROTAVIRUS A NSP1 (MICROBIAL INFECTION).
RX   PubMed=12186937; DOI=10.1128/jvi.76.18.9545-9550.2002;
RA   Graff J.W., Mitzel D.N., Weisend C.M., Flenniken M.L., Hardy M.E.;
RT   "Interferon regulatory factor 3 is a cellular partner of rotavirus NSP1.";
RL   J. Virol. 76:9545-9550(2002).
RN   [17]
RP   INTERACTION WITH TICAM2.
RX   PubMed=14517278; DOI=10.1084/jem.20031023;
RA   Fitzgerald K.A., Rowe D.C., Barnes B.J., Caffrey D.R., Visintin A.,
RA   Latz E., Monks B., Pitha P.M., Golenbock D.T.;
RT   "LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters
RT   TRAM and TRIF.";
RL   J. Exp. Med. 198:1043-1055(2003).
RN   [18]
RP   ERRATUM OF PUBMED:14517278.
RA   Fitzgerald K.A., Rowe D.C., Barnes B.J., Caffrey D.R., Visintin A.,
RA   Latz E., Monks B., Pitha P.M., Golenbock D.T.;
RL   J. Exp. Med. 198:1451-1451(2003).
RN   [19]
RP   PHOSPHORYLATION.
RX   PubMed=12702806; DOI=10.1126/science.1081315;
RA   Sharma S., tenOever B.R., Grandvaux N., Zhou G.-P., Lin R., Hiscott J.;
RT   "Triggering the interferon antiviral response through an IKK-related
RT   pathway.";
RL   Science 300:1148-1151(2003).
RN   [20]
RP   INTERACTION WITH TICAM1.
RX   PubMed=14739303; DOI=10.1074/jbc.m311629200;
RA   Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B.;
RT   "Mechanisms of the TRIF-induced interferon-stimulated response element and
RT   NF-kappaB activation and apoptosis pathways.";
RL   J. Biol. Chem. 279:15652-15661(2004).
RN   [21]
RP   INTERACTION WITH IKBKE AND TBK1.
RX   PubMed=16281057; DOI=10.1038/sj.emboj.7600863;
RA   Huang J., Liu T., Xu L.-G., Chen D., Zhai Z., Shu H.-B.;
RT   "SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-
RT   triggered IRF-3 activation pathways.";
RL   EMBO J. 24:4018-4028(2005).
RN   [22]
RP   INTERACTION WITH MAVS.
RX   PubMed=16153868; DOI=10.1016/j.molcel.2005.08.014;
RA   Xu L.-G., Wang Y.-Y., Han K.-J., Li L.-Y., Zhai Z., Shu H.-B.;
RT   "VISA is an adapter protein required for virus-triggered IFN-beta
RT   Signaling.";
RL   Mol. Cell 19:727-740(2005).
RN   [23]
RP   REVIEW ON FUNCTION.
RX   PubMed=16846591; DOI=10.1016/j.bcp.2006.06.002;
RA   Solis M., Goubau D., Romieu-Mourez R., Genin P., Civas A., Hiscott J.;
RT   "Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and
RT   control of anti-tumor activity in primary macrophages.";
RL   Biochem. Pharmacol. 72:1469-1476(2006).
RN   [24]
RP   REVIEW ON FUNCTION.
RX   PubMed=16979567; DOI=10.1016/j.immuni.2006.08.009;
RA   Honda K., Takaoka A., Taniguchi T.;
RT   "Type I interferon gene induction by the interferon regulatory factor
RT   family of transcription factors.";
RL   Immunity 25:349-360(2006).
RN   [25]
RP   ERRATUM OF PUBMED:16979567.
RA   Honda K., Takaoka A., Taniguchi T.;
RL   Immunity 25:849-849(2006).
RN   [26]
RP   UBIQUITINATION, AND INTERACTION WITH RBCK1.
RX   PubMed=18711448; DOI=10.1038/cr.2008.277;
RA   Zhang M., Tian Y., Wang R.P., Gao D., Zhang Y., Diao F.C., Chen D.Y.,
RA   Zhai Z.H., Shu H.B.;
RT   "Negative feedback regulation of cellular antiviral signaling by RBCK1-
RT   mediated degradation of IRF3.";
RL   Cell Res. 18:1096-1104(2008).
RN   [27]
RP   INTERACTION WITH TRIM21, AND POLYUBIQUITINATION.
RX   PubMed=18641315; DOI=10.4049/jimmunol.181.3.1780;
RA   Higgs R., Ni Gabhann J., Ben Larbi N., Breen E.P., Fitzgerald K.A.,
RA   Jefferies C.A.;
RT   "The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production
RT   post-pathogen recognition by polyubiquitin-mediated degradation of IRF3.";
RL   J. Immunol. 181:1780-1786(2008).
RN   [28]
RP   PHOSPHORYLATION BY IKBKE AND TBK1.
RX   PubMed=19153231; DOI=10.1128/jvi.01875-08;
RA   Prins K.C., Cardenas W.B., Basler C.F.;
RT   "Ebola virus protein VP35 impairs the function of interferon regulatory
RT   factor-activating kinases IKKepsilon and TBK-1.";
RL   J. Virol. 83:3069-3077(2009).
RN   [29]
RP   INTERACTION WITH RIOK3.
RX   PubMed=19557502; DOI=10.1007/s11010-009-0180-8;
RA   Shan J., Wang P., Zhou J., Wu D., Shi H., Huo K.;
RT   "RIOK3 interacts with caspase-10 and negatively regulates the NF-kappaB
RT   signaling pathway.";
RL   Mol. Cell. Biochem. 332:113-120(2009).
RN   [30]
RP   UBIQUITINATION.
RX   PubMed=21167755; DOI=10.1016/j.immuni.2010.11.027;
RA   Yu Y., Hayward G.S.;
RT   "The ubiquitin E3 ligase RAUL negatively regulates type i interferon
RT   through ubiquitination of the transcription factors IRF7 and IRF3.";
RL   Immunity 33:863-877(2010).
RN   [31]
RP   REVIEW ON FUNCTION.
RX   PubMed=20049431; DOI=10.1007/s00262-009-0804-6;
RA   Savitsky D., Tamura T., Yanai H., Taniguchi T.;
RT   "Regulation of immunity and oncogenesis by the IRF transcription factor
RT   family.";
RL   Cancer Immunol. Immunother. 59:489-510(2010).
RN   [32]
RP   INTERACTION WITH HSP90AA1.
RX   PubMed=20628368; DOI=10.1038/cr.2010.103;
RA   Liu X.Y., Wei B., Shi H.X., Shan Y.F., Wang C.;
RT   "Tom70 mediates activation of interferon regulatory factor 3 on
RT   mitochondria.";
RL   Cell Res. 20:994-1011(2010).
RN   [33]
RP   ISGYLATION AT LYS-193; LYS-360 AND LYS-366, MUTAGENESIS OF LYS-193; LYS-360
RP   AND LYS-366, AND INTERACTION WITH HERC5.
RX   PubMed=20308324; DOI=10.1128/mcb.01466-09;
RA   Shi H.X., Yang K., Liu X., Liu X.Y., Wei B., Shan Y.F., Zhu L.H., Wang C.;
RT   "Positive regulation of interferon regulatory factor 3 activation by Herc5
RT   via ISG15 modification.";
RL   Mol. Cell. Biol. 30:2424-2436(2010).
RN   [34]
RP   FUNCTION, SUBUNIT, INTERACTION WITH STING1, PHOSPHORYLATION AT SER-385;
RP   SER-386 AND SER-396, AND MUTAGENESIS OF SER-385 AND SER-386.
RX   PubMed=22394562; DOI=10.1126/scisignal.2002521;
RA   Tanaka Y., Chen Z.J.;
RT   "STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA
RT   signaling pathway.";
RL   Sci. Signal. 5:RA20-RA20(2012).
RN   [35]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [36]
RP   FUNCTION, AND PHOSPHORYLATION AT SER-175 (MICROBIAL INFECTION).
RX   PubMed=24049179; DOI=10.1128/jvi.02355-13;
RA   Wang S., Wang K., Lin R., Zheng C.;
RT   "Herpes simplex virus 1 serine/threonine kinase US3 hyperphosphorylates
RT   IRF3 and inhibits beta interferon production.";
RL   J. Virol. 87:12814-12827(2013).
RN   [37]
RP   INTERACTION WITH DDX3X AND IKBKE, AND PHOSPHORYLATION AT SER-396.
RX   PubMed=23478265; DOI=10.1128/mcb.01603-12;
RA   Gu L., Fullam A., Brennan R., Schroder M.;
RT   "Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon
RT   regulatory factor 3 activation.";
RL   Mol. Cell. Biol. 33:2004-2015(2013).
RN   [38]
RP   PHOSPHORYLATION AT THR-3; SER-14; THR-75; SER-97; THR-180; SER-188;
RP   THR-237; THR-244; THR-253; SER-398; THR-404 AND SER-427, PHOSPHORYLATION AT
RP   SER-386 BY TBK1, AND MUTAGENESIS OF SER-386.
RX   PubMed=23746807; DOI=10.1016/j.str.2013.04.025;
RA   Shu C., Sankaran B., Chaton C.T., Herr A.B., Mishra A., Peng J., Li P.;
RT   "Structural insights into the functions of TBK1 in innate antimicrobial
RT   immunity.";
RL   Structure 21:1137-1148(2013).
RN   [39]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [40]
RP   HOMODIMERIZATION, AND INTERACTION WITH TRIM21 AND ULK1.
RX   PubMed=26347139; DOI=10.1083/jcb.201503023;
RA   Kimura T., Jain A., Choi S.W., Mandell M.A., Schroder K., Johansen T.,
RA   Deretic V.;
RT   "TRIM-mediated precision autophagy targets cytoplasmic regulators of innate
RT   immunity.";
RL   J. Cell Biol. 210:973-989(2015).
RN   [41]
RP   FUNCTION, INTERACTION WITH BCL2; BAX AND HSP90AA1, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=25609812; DOI=10.1128/jvi.02959-14;
RA   Wei B., Cui Y., Huang Y., Liu H., Li L., Li M., Ruan K.C., Zhou Q.,
RA   Wang C.;
RT   "Tom70 mediates Sendai virus-induced apoptosis on mitochondria.";
RL   J. Virol. 89:3804-3818(2015).
RN   [42]
RP   INTERACTION WITH DDX3X AND TRAF3.
RX   PubMed=27980081; DOI=10.1042/bcj20160956;
RA   Gu L., Fullam A., McCormack N., Hoehn Y., Schroeder M.;
RT   "DDX3 directly regulates TRAF3 ubiquitination and acts as a scaffold to co-
RT   ordinate assembly of signalling complexes downstream from MAVS.";
RL   Biochem. J. 474:571-587(2017).
RN   [43]
RP   INTERACTION WITH STING1 AND ZDHHC11, AND REGION.
RX   PubMed=28331227; DOI=10.1038/leu.2017.94;
RA   Dzikiewicz-Krawczyk A., Kok K., Slezak-Prochazka I., Robertus J.L.,
RA   Bruining J., Tayari M.M., Rutgers B., de Jong D., Koerts J., Seitz A.,
RA   Li J., Tillema B., Guikema J.E., Nolte I.M., Diepstra A., Visser L.,
RA   Kluiver J., van den Berg A.;
RT   "ZDHHC11 and ZDHHC11B are critical novel components of the oncogenic MYC-
RT   miR-150-MYB network in Burkitt lymphoma.";
RL   Leukemia 31:1470-1473(2017).
RN   [44]
RP   FUNCTION, INDUCTION BY DSRNA, AND INTERACTION WITH IRF3.
RX   PubMed=29802199; DOI=10.1074/jbc.ra117.001491;
RA   Ambrose R.L., Liu Y.C., Adams T.E., Bean A.G.D., Stewart C.R.;
RT   "C6orf106 is a novel inhibitor of the interferon-regulatory factor 3-
RT   dependent innate antiviral response.";
RL   J. Biol. Chem. 293:10561-10573(2018).
RN   [45]
RP   INTERACTION WITH SENECA VALLEY VIRUS PROTEASE 3C (MICROBIAL INFECTION).
RX   PubMed=29427864; DOI=10.1016/j.virol.2018.01.028;
RA   Xue Q., Liu H., Zhu Z., Yang F., Ma L., Cai X., Xue Q., Zheng H.;
RT   "Seneca Valley Virus 3Cpro abrogates the IRF3- and IRF7-mediated innate
RT   immune response by degrading IRF3 and IRF7.";
RL   Virology 518:1-7(2018).
RN   [46]
RP   INVOLVEMENT IN IIAE7, VARIANT IIAE7 GLN-285, AND CHARACTERIZATION OF
RP   VARIANT IIAE7 GLN-285.
RX   PubMed=26216125; DOI=10.1084/jem.20142274;
RA   Andersen L.L., Moerk N., Reinert L.S., Kofod-Olsen E., Narita R.,
RA   Joergensen S.E., Skipper K.A., Hoening K., Gad H.H., Oestergaard L.,
RA   Oerntoft T.F., Hornung V., Paludan S.R., Mikkelsen J.G., Fujita T.,
RA   Christiansen M., Hartmann R., Mogensen T.H.;
RT   "Functional IRF3 deficiency in a patient with herpes simplex
RT   encephalitis.";
RL   J. Exp. Med. 212:1371-1379(2015).
RN   [47]
RP   FUNCTION, ACTIVITY REGULATION, INTERACTION WITH STING1; MAVS AND TICAM1,
RP   PHOSPHORYLATION AT SER-385; SER-386 AND SER-396, AND MUTAGENESIS OF SER-385
RP   AND SER-386.
RX   PubMed=25636800; DOI=10.1126/science.aaa2630;
RA   Liu S., Cai X., Wu J., Cong Q., Chen X., Li T., Du F., Ren J., Wu Y.T.,
RA   Grishin N.V., Chen Z.J.;
RT   "Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF
RT   induces IRF3 activation.";
RL   Science 347:AAA2630-AAA2630(2015).
RN   [48]
RP   FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH LYAR.
RX   PubMed=31413131; DOI=10.1128/jvi.00769-19;
RA   Yang C., Liu X., Cheng T., Xiao R., Gao Q., Ming F., Jin M., Chen H.,
RA   Zhou H.;
RT   "LYAR suppresses interferon-beta induction by targeting phosphorylated
RT   IRF3.";
RL   J. Virol. 0:0-0(2019).
RN   [49]
RP   INTERACTION WITH HERPES SIMPLEX VIRUS 2 (HHV-2) PROTEIN ICP27 (MICROBIAL
RP   INFECTION).
RX   PubMed=30863402; DOI=10.3389/fimmu.2019.00290;
RA   Guan X., Zhang M., Fu M., Luo S., Hu Q.;
RT   "Herpes Simplex Virus Type 2 Immediate Early Protein ICP27 Inhibits IFN-
RT   beta Production in Mucosal Epithelial Cells by Antagonizing IRF3
RT   Activation.";
RL   Front. Immunol. 10:290-290(2019).
RN   [50]
RP   INTERACTION WITH HUMAN CYTOMEGALOVIRUS PROTEIN UL44 (MICROBIAL INFECTION).
RX   PubMed=30867312; DOI=10.1128/jvi.00181-19;
RA   Fu Y.Z., Su S., Zou H.M., Guo Y., Wang S.Y., Li S., Luo M.H., Wang Y.Y.;
RT   "Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral
RT   Immune Responses by Suppressing IRF3- and NF-kappaB-Mediated
RT   Transcription.";
RL   J. Virol. 93:0-0(2019).
RN   [51]
RP   PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-116 AND 121-ASP--ASP-125.
RX   PubMed=30878284; DOI=10.1016/j.molcel.2019.02.013;
RA   Ning X., Wang Y., Jing M., Sha M., Lv M., Gao P., Zhang R., Huang X.,
RA   Feng J.M., Jiang Z.;
RT   "Apoptotic caspases suppress type i interferon production via the cleavage
RT   of cGAS, MAVS, and IRF3.";
RL   Mol. Cell 74:19-31(2019).
RN   [52]
RP   FUNCTION, INTERACTION WITH DDX56, AND SUBCELLULAR LOCATION.
RX   PubMed=31340999; DOI=10.1242/jcs.230409;
RA   Li D., Fu S., Wu Z., Yang W., Ru Y., Shu H., Liu X., Zheng H.;
RT   "DDX56 inhibits type I interferon by disrupting assembly of IRF3-IPO5 to
RT   inhibit IRF3 nucleus import.";
RL   J. Cell Sci. 133:0-0(2019).
RN   [53]
RP   ISGYLATION (MICROBIAL INFECTION).
RX   PubMed=32726803; DOI=10.1038/s41586-020-2601-5;
RA   Shin D., Mukherjee R., Grewe D., Bojkova D., Baek K., Bhattacharya A.,
RA   Schulz L., Widera M., Mehdipour A.R., Tascher G., Geurink P.P., Wilhelm A.,
RA   van der Heden van Noort G.J., Ovaa H., Mueller S., Knobeloch K.P.,
RA   Rajalingam K., Schulman B.A., Cinatl J., Hummer G., Ciesek S., Dikic I.;
RT   "Papain-like protease regulates SARS-CoV-2 viral spread and innate
RT   immunity.";
RL   Nature 587:657-662(2020).
RN   [54]
RP   FUNCTION, AND ACTIVITY REGULATION (MICROBIAL INFECTION).
RX   PubMed=33440148; DOI=10.1016/j.celrep.2020.108628;
RA   Yin X., Riva L., Pu Y., Martin-Sancho L., Kanamune J., Yamamoto Y.,
RA   Sakai K., Gotoh S., Miorin L., De Jesus P.D., Yang C.C., Herbert K.M.,
RA   Yoh S., Hultquist J.F., Garcia-Sastre A., Chanda S.K.;
RT   "MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial
RT   Cells.";
RL   Cell Rep. 34:108628-108628(2021).
RN   [55]
RP   INTERACTION WITH NBR1.
RX   PubMed=35914352; DOI=10.1016/j.bbrc.2022.07.043;
RA   Cai Y., Zhu Y., Zheng J., Zhang Y., Chen W.;
RT   "NBR1 mediates autophagic degradation of IRF3 to negatively regulate type I
RT   interferon production.";
RL   Biochem. Biophys. Res. Commun. 623:140-147(2022).
RN   [56]
RP   INTERACTION WITH MERS-COV PROTEIN N (MICROBIAL INFECTION), AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=35922005; DOI=10.1038/s41586-022-05148-4;
RA   Chu H., Hou Y., Yang D., Wen L., Shuai H., Yoon C., Shi J., Chai Y.,
RA   Yuen T.T., Hu B., Li C., Zhao X., Wang Y., Huang X., Lee K.S., Luo C.,
RA   Cai J.P., Poon V.K., Chan C.C., Zhang A.J., Yuan S., Sit K.Y., Foo D.C.,
RA   Au W.K., Wong K.K., Zhou J., Kok K.H., Jin D.Y., Chan J.F., Yuen K.Y.;
RT   "Coronaviruses exploit a host cysteine-aspartic protease for replication.";
RL   Nature 0:0-0(2022).
RN   [57]
RP   FUNCTION, ACTIVITY REGULATION, SUBUNIT, SUBCELLULAR LOCATION,
RP   PYROPHOSPHORYLATION AT SER-386, PHOSPHORYLATION AT SER-386 AND SER-396, AND
RP   MUTAGENESIS OF SER-386 AND THR-390.
RX   PubMed=36603579; DOI=10.1016/j.molcel.2022.12.007;
RA   Yang S., Jin S., Xian H., Zhao Z., Wang L., Wu Y., Zhou L., Li M., Cui J.;
RT   "Metabolic enzyme UAP1 mediates IRF3 pyrophosphorylation to facilitate
RT   innate immune response.";
RL   Mol. Cell 83:298-313(2023).
RN   [58]
RP   X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 175-427, AND DISULFIDE BOND.
RX   PubMed=14555995; DOI=10.1038/nsb1001;
RA   Takahasi K., Suzuki N.N., Horiuchi M., Mori M., Suhara W., Okabe Y.,
RA   Fukuhara Y., Terasawa H., Akira S., Fujita T., Inagaki F.;
RT   "X-ray crystal structure of IRF-3 and its functional implications.";
RL   Nat. Struct. Biol. 10:922-927(2003).
RN   [59]
RP   X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 173-427, AND DISULFIDE BOND.
RX   PubMed=14555996; DOI=10.1038/nsb1002;
RA   Qin B.Y., Liu C., Lam S.S., Srinath H., Delston R., Correia J.J.,
RA   Derynck R., Lin K.;
RT   "Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-
RT   induced phosphoactivation.";
RL   Nat. Struct. Biol. 10:913-921(2003).
RN   [60]
RP   X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 1-112.
RX   PubMed=15510218; DOI=10.1038/sj.emboj.7600453;
RA   Panne D., Maniatis T., Harrison S.C.;
RT   "Crystal structure of ATF-2/c-Jun and IRF-3 bound to the interferon-beta
RT   enhancer.";
RL   EMBO J. 23:4384-4393(2004).
RN   [61]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 173-394, FUNCTION, AND INTERACTION
RP   WITH CREBBP.
RX   PubMed=16154084; DOI=10.1016/j.str.2005.06.011;
RA   Qin B.Y., Liu C., Srinath H., Lam S.S., Correia J.J., Derynck R., Lin K.;
RT   "Crystal structure of IRF-3 in complex with CBP.";
RL   Structure 13:1269-1277(2005).
RN   [62] {ECO:0007744|PDB:5JEJ, ECO:0007744|PDB:5JEK, ECO:0007744|PDB:5JEL, ECO:0007744|PDB:5JEM, ECO:0007744|PDB:5JEO, ECO:0007744|PDB:5JER}
RP   X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 189-427 IN COMPLEX WITH CREBBP;
RP   MAVS; STING1 OR TICAM1, X-RAY CRYSTALLOGRAPHY (2.91 ANGSTROMS) OF 189-427
RP   IN COMPLEX WITH ROTAVIRUS A NSP1 (MICROBIAL INFECTION), FUNCTION, ACTIVITY
RP   REGULATION, INTERACTION WITH CREBBP; MAVS; STING1 AND TICAM1, INTERACTION
RP   WITH ROTAVIRUS A NSP1 (MICROBIAL INFECTION), PHOSPHORYLATION AT SER-386 AND
RP   SER-396, AND MUTAGENESIS OF ARG-285; HIS-288; HIS-290; LYS-313; SER-386 AND
RP   SER-396.
RX   PubMed=27302953; DOI=10.1073/pnas.1603269113;
RA   Zhao B., Shu C., Gao X., Sankaran B., Du F., Shelton C.L., Herr A.B.,
RA   Ji J.Y., Li P.;
RT   "Structural basis for concerted recruitment and activation of IRF-3 by
RT   innate immune adaptor proteins.";
RL   Proc. Natl. Acad. Sci. U.S.A. 113:E3403-E3412(2016).
RN   [63]
RP   VARIANTS GLU-49 DEL; 145-GLY--GLU-200 DEL; LYS-146; GLN-227; GLN-285 AND
RP   VAL-401, CHARACTERIZATION OF VARIANTS GLU-49 DEL; 145-GLY--GLU-200 DEL;
RP   LYS-146; GLN-227; GLN-285 AND VAL-401, AND FUNCTION.
RX   PubMed=32972995; DOI=10.1126/science.abd4570;
RG   COVID-STORM Clinicians;
RG   COVID Clinicians;
RG   Imagine COVID Group;
RG   French COVID Cohort Study Group;
RG   CoV-Contact Cohort;
RG   Amsterdam UMC Covid-19 Biobank;
RG   COVID Human Genetic Effort;
RG   NIAID-USUHS/TAGC COVID Immunity Group;
RA   Zhang Q., Bastard P., Liu Z., Le Pen J., Moncada-Velez M., Chen J.,
RA   Ogishi M., Sabli I.K.D., Hodeib S., Korol C., Rosain J., Bilguvar K.,
RA   Ye J., Bolze A., Bigio B., Yang R., Arias A.A., Zhou Q., Zhang Y.,
RA   Onodi F., Korniotis S., Karpf L., Philippot Q., Chbihi M., Bonnet-Madin L.,
RA   Dorgham K., Smith N., Schneider W.M., Razooky B.S., Hoffmann H.H.,
RA   Michailidis E., Moens L., Han J.E., Lorenzo L., Bizien L., Meade P.,
RA   Neehus A.L., Ugurbil A.C., Corneau A., Kerner G., Zhang P., Rapaport F.,
RA   Seeleuthner Y., Manry J., Masson C., Schmitt Y., Schlueter A., Le Voyer T.,
RA   Khan T., Li J., Fellay J., Roussel L., Shahrooei M., Alosaimi M.F.,
RA   Mansouri D., Al-Saud H., Al-Mulla F., Almourfi F., Al-Muhsen S.Z.,
RA   Alsohime F., Al Turki S., Hasanato R., van de Beek D., Biondi A.,
RA   Bettini L.R., D'Angio' M., Bonfanti P., Imberti L., Sottini A., Paghera S.,
RA   Quiros-Roldan E., Rossi C., Oler A.J., Tompkins M.F., Alba C.,
RA   Vandernoot I., Goffard J.C., Smits G., Migeotte I., Haerynck F.,
RA   Soler-Palacin P., Martin-Nalda A., Colobran R., Morange P.E., Keles S.,
RA   Coelkesen F., Ozcelik T., Yasar K.K., Senoglu S., Karabela S.N.,
RA   Rodriguez-Gallego C., Novelli G., Hraiech S., Tandjaoui-Lambiotte Y.,
RA   Duval X., Laouenan C., Snow A.L., Dalgard C.L., Milner J.D., Vinh D.C.,
RA   Mogensen T.H., Marr N., Spaan A.N., Boisson B., Boisson-Dupuis S.,
RA   Bustamante J., Puel A., Ciancanelli M.J., Meyts I., Maniatis T.,
RA   Soumelis V., Amara A., Nussenzweig M., Garcia-Sastre A., Krammer F.,
RA   Pujol A., Duffy D., Lifton R.P., Zhang S.Y., Gorochov G., Beziat V.,
RA   Jouanguy E., Sancho-Shimizu V., Rice C.M., Abel L., Notarangelo L.D.,
RA   Cobat A., Su H.C., Casanova J.L.;
RT   "Inborn errors of type I IFN immunity in patients with life-threatening
RT   COVID-19.";
RL   Science 370:0-0(2020).
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 (PubMed:22394562,
CC       PubMed:24049179, PubMed:25636800, PubMed:27302953, PubMed:31340999,
CC       PubMed:36603579, PubMed:8524823). Regulates the transcription of type I
CC       IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by
CC       binding to an interferon-stimulated response element (ISRE) in their
CC       promoters (PubMed:11846977, PubMed:16846591, PubMed:16979567,
CC       PubMed:20049431, PubMed:32972995, PubMed:36603579, PubMed:8524823).
CC       Acts as a more potent activator of the IFN-beta (IFNB) gene than the
CC       IFN-alpha (IFNA) gene and plays a critical role in both the early and
CC       late phases of the IFNA/B gene induction (PubMed:16846591,
CC       PubMed:16979567, PubMed:20049431, PubMed:36603579). Found in an
CC       inactive form in the cytoplasm of uninfected cells and following viral
CC       infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR)
CC       signaling, is phosphorylated by IKBKE and TBK1 kinases
CC       (PubMed:22394562, PubMed:25636800, PubMed:27302953, PubMed:36603579).
CC       This induces a conformational change, leading to its dimerization and
CC       nuclear localization and association with CREB binding protein (CREBBP)
CC       to form dsRNA-activated factor 1 (DRAF1), a complex which activates the
CC       transcription of the type I IFN and ISG genes (PubMed:16154084,
CC       PubMed:27302953, PubMed:33440148, PubMed:36603579). Can activate
CC       distinct gene expression programs in macrophages and can induce
CC       significant apoptosis in primary macrophages (PubMed:16846591). In
CC       response to Sendai virus infection, is recruited by TOMM70:HSP90AA1 to
CC       mitochondrion and forms an apoptosis complex TOMM70:HSP90AA1:IRF3:BAX
CC       inducing apoptosis (PubMed:25609812). Key transcription factor
CC       regulating the IFN response during SARS-CoV-2 infection
CC       (PubMed:33440148). {ECO:0000269|PubMed:16154084,
CC       ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:24049179,
CC       ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:25636800,
CC       ECO:0000269|PubMed:27302953, ECO:0000269|PubMed:31340999,
CC       ECO:0000269|PubMed:31413131, ECO:0000269|PubMed:32972995,
CC       ECO:0000269|PubMed:33440148, ECO:0000269|PubMed:36603579,
CC       ECO:0000269|PubMed:8524823, ECO:0000303|PubMed:11846977,
CC       ECO:0000303|PubMed:16846591, ECO:0000303|PubMed:16979567,
CC       ECO:0000303|PubMed:20049431}.
CC   -!- ACTIVITY REGULATION: In the absence of viral infection, maintained as a
CC       monomer in an autoinhibited state (PubMed:16846591, PubMed:16979567,
CC       PubMed:20049431). Phosphorylation by TBK1 and IKBKE disrupts this
CC       autoinhibition leading to the liberation of the DNA-binding and
CC       dimerization activities and its nuclear localization where it can
CC       activate type I IFN and ISG genes (PubMed:25636800). Phosphorylation
CC       and activation follow the following steps: innate adapter proteins,
CC       such as MAVS, STING1 or TICAM1, are first activated by viral RNA,
CC       cytosolic DNA and bacterial lipopolysaccharide (LPS), respectively,
CC       leading to activation of the kinases TBK1 and IKBKE (PubMed:25636800,
CC       PubMed:36603579). These kinases then phosphorylate the adapter proteins
CC       on their pLxIS motif, leading to recruitment of IRF3, thereby licensing
CC       IRF3 for phosphorylation by TBK1 (PubMed:25636800, PubMed:36603579).
CC       Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes,
CC       and then enters the nucleus to induce IFNs (PubMed:25636800,
CC       PubMed:27302953). {ECO:0000269|PubMed:25636800,
CC       ECO:0000269|PubMed:27302953, ECO:0000269|PubMed:33440148,
CC       ECO:0000269|PubMed:36603579, ECO:0000303|PubMed:16846591,
CC       ECO:0000303|PubMed:16979567, ECO:0000303|PubMed:20049431}.
CC   -!- ACTIVITY REGULATION: (Microbial infection) Activated upon coronavirus
CC       SARS-CoV-2 infection. {ECO:0000269|PubMed:33440148}.
CC   -!- SUBUNIT: Monomer (PubMed:16846591, PubMed:16979567, PubMed:20049431,
CC       PubMed:36603579). Homodimer; phosphorylation-induced (PubMed:22394562,
CC       PubMed:25636800, PubMed:26347139, PubMed:36603579). Interacts (when
CC       phosphorylated) with CREBBP (PubMed:16154084, PubMed:27302953).
CC       Interacts with MAVS (via phosphorylated pLxIS motif) (PubMed:16153868,
CC       PubMed:25636800, PubMed:27302953). Interacts with TICAM1 (via
CC       phosphorylated pLxIS motif) (PubMed:12471095, PubMed:14739303,
CC       PubMed:25636800, PubMed:27302953). Interacts with STING1 (via
CC       phosphorylated pLxIS motif) (PubMed:22394562, PubMed:25636800,
CC       PubMed:27302953, PubMed:28331227). Interacts with IKBKE and TBK1
CC       (PubMed:16281057, PubMed:23478265, PubMed:25636800). Interacts with
CC       TICAM2 (PubMed:14517278). Interacts with RBCK1 (PubMed:18711448).
CC       Interacts with HERC5 (PubMed:20308324). Interacts with DDX3X
CC       (phosphorylated at 'Ser-102'); the interaction allows the
CC       phosphorylation and activation of IRF3 by IKBKE (PubMed:23478265,
CC       PubMed:27980081). Interacts with TRIM21 and ULK1, in the presence of
CC       TRIM21; this interaction leads to IRF3 degradation by autophagy
CC       (PubMed:18641315, PubMed:26347139). Interacts with RIOK3; RIOK3
CC       probably mediates the interaction of TBK1 with IRF3 (PubMed:19557502).
CC       Interacts with ILRUN; the interaction inhibits IRF3 binding to its DNA
CC       consensus sequence (PubMed:29802199). Interacts with LYAR; this
CC       interaction impairs IRF3 DNA-binding activity (PubMed:31413131).
CC       Interacts with TRAF3 (PubMed:27980081). Interacts with ZDHHC11; ZDHHC11
CC       recruits IRF3 to STING1 upon DNA virus infection and thereby promotes
CC       IRF3 activation (PubMed:28331227). Interacts with HSP90AA1; the
CC       interaction mediates IRF3 association with TOMM70 (PubMed:20628368,
CC       PubMed:25609812). Interacts with BCL2; the interaction decreases upon
CC       Sendai virus infection (PubMed:25609812). Interacts with BAX; the
CC       interaction is direct, increases upon Sendai virus infection and
CC       mediates the formation of the apoptosis complex
CC       TOMM70:HSP90AA1:IRF3:BAX (PubMed:25609812). Interacts with DDX56
CC       (PubMed:31340999). Interacts with NBR1 (PubMed:35914352).
CC       {ECO:0000269|PubMed:12471095, ECO:0000269|PubMed:14517278,
CC       ECO:0000269|PubMed:14739303, ECO:0000269|PubMed:16153868,
CC       ECO:0000269|PubMed:16154084, ECO:0000269|PubMed:16281057,
CC       ECO:0000269|PubMed:18641315, ECO:0000269|PubMed:18711448,
CC       ECO:0000269|PubMed:19557502, ECO:0000269|PubMed:20308324,
CC       ECO:0000269|PubMed:20628368, ECO:0000269|PubMed:22394562,
CC       ECO:0000269|PubMed:23478265, ECO:0000269|PubMed:25609812,
CC       ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:26347139,
CC       ECO:0000269|PubMed:27302953, ECO:0000269|PubMed:27980081,
CC       ECO:0000269|PubMed:28331227, ECO:0000269|PubMed:29802199,
CC       ECO:0000269|PubMed:31340999, ECO:0000269|PubMed:31413131,
CC       ECO:0000269|PubMed:35914352, ECO:0000269|PubMed:36603579,
CC       ECO:0000303|PubMed:16846591, ECO:0000303|PubMed:16979567,
CC       ECO:0000303|PubMed:20049431}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with rotavirus A NSP1 (via
CC       pLxIS motif); this interaction leads to the proteasome-dependent
CC       degradation of IRF3. {ECO:0000269|PubMed:12186937,
CC       ECO:0000269|PubMed:27302953}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with herpes virus 8/HHV-8
CC       protein VIRF1 (PubMed:11314014). {ECO:0000269|PubMed:11314014}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with Seneca Valley virus
CC       protease 3C; this interaction is involved in the suppression of IRF3
CC       expression and phosphorylation by the virus.
CC       {ECO:0000269|PubMed:29427864}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with herpes virus 2/HHV-2
CC       protein ICP27; this interaction inhibits IRF3 phosphorylation and
CC       nuclear translocation. {ECO:0000269|PubMed:30863402}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with human cytomegalovirus
CC       protein UL44; this interaction prevents IRF3 binding to its promoters.
CC       {ECO:0000269|PubMed:30867312}.
CC   -!- SUBUNIT: (Microbial infection) Interacts with the two fragments of
CC       MERS-COV protein N produced by CASP6 through proteolytic cleavage; both
CC       interactions inhibit IRF3 nuclear translocation after activation and
CC       IFN signaling. {ECO:0000269|PubMed:35922005}.
CC   -!- INTERACTION:
CC       Q14653; Q92793: CREBBP; NbExp=12; IntAct=EBI-2650369, EBI-81215;
CC       Q14653; Q9Y3R0: GRIP1; NbExp=2; IntAct=EBI-2650369, EBI-5349621;
CC       Q14653; Q14164: IKBKE; NbExp=2; IntAct=EBI-2650369, EBI-307369;
CC       Q14653; P10914: IRF1; NbExp=5; IntAct=EBI-2650369, EBI-1055781;
CC       Q14653; Q14653: IRF3; NbExp=18; IntAct=EBI-2650369, EBI-2650369;
CC       Q14653; P05161: ISG15; NbExp=2; IntAct=EBI-2650369, EBI-746466;
CC       Q14653; P52292: KPNA2; NbExp=2; IntAct=EBI-2650369, EBI-349938;
CC       Q14653; O60684: KPNA6; NbExp=3; IntAct=EBI-2650369, EBI-359923;
CC       Q14653; Q9Y5Q3: MAFB; NbExp=4; IntAct=EBI-2650369, EBI-3649340;
CC       Q14653; P67775: PPP2CA; NbExp=4; IntAct=EBI-2650369, EBI-712311;
CC       Q14653; P06400: RB1; NbExp=2; IntAct=EBI-2650369, EBI-491274;
CC       Q14653; P28749: RBL1; NbExp=2; IntAct=EBI-2650369, EBI-971402;
CC       Q14653; O14730: RIOK3; NbExp=6; IntAct=EBI-2650369, EBI-1047061;
CC       Q14653; O43765: SGTA; NbExp=3; IntAct=EBI-2650369, EBI-347996;
CC       Q14653; Q9UHD2: TBK1; NbExp=10; IntAct=EBI-2650369, EBI-356402;
CC       Q14653; PRO_0000037311 [P0C6X7]: rep; Xeno; NbExp=5; IntAct=EBI-2650369, EBI-25474079;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10805757,
CC       ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:31340999,
CC       ECO:0000269|PubMed:31413131, ECO:0000269|PubMed:35922005,
CC       ECO:0000269|PubMed:36603579, ECO:0000305|PubMed:25636800}. Nucleus
CC       {ECO:0000269|PubMed:10805757, ECO:0000269|PubMed:31340999,
CC       ECO:0000269|PubMed:31413131, ECO:0000269|PubMed:35922005,
CC       ECO:0000269|PubMed:36603579, ECO:0000305|PubMed:25636800}.
CC       Mitochondrion {ECO:0000269|PubMed:25609812}. Note=Shuttles between
CC       cytoplasmic and nuclear compartments, with export being the prevailing
CC       effect (PubMed:10805757, PubMed:35922005). When activated, IRF3
CC       interaction with CREBBP prevents its export to the cytoplasm
CC       (PubMed:10805757). Recruited to mitochondria via TOMM70:HSP90AA1 upon
CC       Sendai virus infection (PubMed:25609812). {ECO:0000269|PubMed:10805757,
CC       ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:35922005}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=5;
CC       Name=1;
CC         IsoId=Q14653-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q14653-2; Sequence=VSP_043319;
CC       Name=3;
CC         IsoId=Q14653-3; Sequence=VSP_046911, VSP_043319;
CC       Name=4;
CC         IsoId=Q14653-4; Sequence=VSP_046912;
CC       Name=5;
CC         IsoId=Q14653-5; Sequence=VSP_047690, VSP_047691;
CC   -!- TISSUE SPECIFICITY: Expressed constitutively in a variety of tissues.
CC       {ECO:0000269|PubMed:8524823}.
CC   -!- PTM: Constitutively phosphorylated on many Ser/Thr residues
CC       (PubMed:22394562, PubMed:23478265, PubMed:23746807). Activated
CC       following phosphorylation by TBK1 and IKBKE (PubMed:23478265,
CC       PubMed:23746807, PubMed:25636800, PubMed:36603579). Innate adapter
CC       proteins, such as MAVS, STING1 or TICAM1, are first activated by viral
CC       RNA, cytosolic DNA, and bacterial lipopolysaccharide (LPS),
CC       respectively, leading to activation of the kinases TBK1 and IKBKE
CC       (PubMed:25636800). These kinases then phosphorylate the adapter
CC       proteins on the pLxIS motif, leading to recruitment of IRF3, thereby
CC       licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800).
CC       Phosphorylation at Ser-386 is followed by pyrophosphorylation at the
CC       same residue, promoting phosphorylation at Ser-396 (PubMed:36603579).
CC       Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes,
CC       and then enters the nucleus to induce IFNs (PubMed:25636800,
CC       PubMed:36603579). {ECO:0000269|PubMed:22394562,
CC       ECO:0000269|PubMed:23478265, ECO:0000269|PubMed:23746807,
CC       ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:36603579}.
CC   -!- PTM: Pyrophosphorylated by UAP1 following phosphorylation at Ser-386 by
CC       TBK1 (PubMed:36603579). Pyrophosphorylation promotes subsequent
CC       phosphorylation at Ser-396, leading to homodimerization of IRF3
CC       (PubMed:36603579). {ECO:0000269|PubMed:36603579}.
CC   -!- PTM: Acetylation at Lys-366 by KAT8 inhibits recruimtent to promoters
CC       and transcription factor activity. Acetylation by KAT8 is promoted by
CC       phosphorylation at Ser-396. {ECO:0000250|UniProtKB:P70671}.
CC   -!- PTM: Ubiquitinated; ubiquitination involves RBCK1 leading to
CC       proteasomal degradation (PubMed:18711448). Polyubiquitinated;
CC       ubiquitination involves TRIM21 leading to proteasomal degradation
CC       (PubMed:18641315). Ubiquitinated by UBE3C, leading to its degradation
CC       (PubMed:21167755). {ECO:0000269|PubMed:18641315,
CC       ECO:0000269|PubMed:18711448, ECO:0000269|PubMed:21167755}.
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:0000269|PubMed:18641315, ECO:0000269|PubMed:18711448,
CC       ECO:0000269|PubMed:20308324}.
CC   -!- PTM: Proteolytically cleaved by apoptotic caspases during apoptosis,
CC       leading to its inactivation (PubMed:30878284). Cleavage by CASP3 during
CC       virus-induced apoptosis inactivates it, preventing cytokine
CC       overproduction (PubMed:30878284). {ECO:0000269|PubMed:30878284}.
CC   -!- PTM: (Microbial infection) ISGylated. ISGylation is cleaved and removed
CC       by SARS-COV-2 nsp3 which attenuates type I interferon responses.
CC       {ECO:0000269|PubMed:32726803}.
CC   -!- PTM: (Microbial infection) Phosphorylation and subsequent activation of
CC       IRF3 is inhibited by vaccinia virus protein E3.
CC       {ECO:0000269|PubMed:11124948}.
CC   -!- PTM: (Microbial infection) Phosphorylated by herpes simplex virus
CC       1/HHV-1 US3 at Ser-175 to prevent IRF3 activation.
CC       {ECO:0000269|PubMed:24049179}.
CC   -!- DISEASE: Encephalopathy, acute, infection-induced, 7, herpes-specific
CC       (IIAE7) [MIM:616532]: A rare complication of human herpesvirus 1 (HHV-
CC       1) infection, occurring in only a small minority of HHV-1 infected
CC       individuals. It is characterized by hemorrhagic necrosis of parts of
CC       the temporal and frontal lobes. Onset is over several days and involves
CC       fever, headache, seizures, stupor, and often coma, frequently with a
CC       fatal outcome. {ECO:0000269|PubMed:26216125}. Note=Disease
CC       susceptibility is associated with variants affecting the gene
CC       represented in this entry.
CC   -!- SIMILARITY: Belongs to the IRF family. {ECO:0000255|PROSITE-
CC       ProRule:PRU00840}.
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DR   EMBL; Z56281; CAA91227.1; -; mRNA.
DR   EMBL; AB102884; BAD89413.1; -; mRNA.
DR   EMBL; AB102886; BAD89415.1; -; mRNA.
DR   EMBL; AB102887; BAD89416.1; -; mRNA.
DR   EMBL; AK292027; BAF84716.1; -; mRNA.
DR   EMBL; AK314421; BAG37040.1; -; mRNA.
DR   EMBL; AC011495; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471177; EAW52510.1; -; Genomic_DNA.
DR   EMBL; BC000660; AAH00660.1; -; mRNA.
DR   EMBL; BC071721; AAH71721.1; -; mRNA.
DR   EMBL; U86636; AAC68818.1; -; Genomic_DNA.
DR   CCDS; CCDS12775.1; -. [Q14653-1]
DR   CCDS; CCDS56099.1; -. [Q14653-2]
DR   CCDS; CCDS59407.1; -. [Q14653-3]
DR   CCDS; CCDS59409.1; -. [Q14653-4]
DR   RefSeq; NP_001184051.1; NM_001197122.1. [Q14653-4]
DR   RefSeq; NP_001184052.1; NM_001197123.1.
DR   RefSeq; NP_001184053.1; NM_001197124.1. [Q14653-2]
DR   RefSeq; NP_001184054.1; NM_001197125.1.
DR   RefSeq; NP_001184055.1; NM_001197126.1.
DR   RefSeq; NP_001184056.1; NM_001197127.1. [Q14653-3]
DR   RefSeq; NP_001184057.1; NM_001197128.1. [Q14653-3]
DR   RefSeq; NP_001562.1; NM_001571.5. [Q14653-1]
DR   RefSeq; XP_006723260.1; XM_006723197.1. [Q14653-4]
DR   RefSeq; XP_006723261.1; XM_006723198.1. [Q14653-4]
DR   RefSeq; XP_016882255.1; XM_017026766.1. [Q14653-1]
DR   RefSeq; XP_016882256.1; XM_017026767.1. [Q14653-1]
DR   PDB; 1J2F; X-ray; 2.30 A; A/B=175-427.
DR   PDB; 1QWT; X-ray; 2.10 A; A/B=173-427.
DR   PDB; 1T2K; X-ray; 3.00 A; A/B=1-112.
DR   PDB; 1ZOQ; X-ray; 2.37 A; A/B=196-386.
DR   PDB; 2O61; X-ray; 2.80 A; A=9-111.
DR   PDB; 2O6G; X-ray; 3.10 A; E/F/G/H=1-123.
DR   PDB; 2PI0; X-ray; 2.31 A; A/B/C/D=1-113.
DR   PDB; 3A77; X-ray; 1.80 A; A/B/C/D=189-427.
DR   PDB; 3QU6; X-ray; 2.30 A; A/B/C=1-113.
DR   PDB; 5JEJ; X-ray; 2.00 A; A/B=189-427.
DR   PDB; 5JEK; X-ray; 2.40 A; A/B=189-427.
DR   PDB; 5JEL; X-ray; 1.60 A; A=189-427.
DR   PDB; 5JEM; X-ray; 2.50 A; A/B/E/G=189-398.
DR   PDB; 5JEO; X-ray; 1.72 A; A=189-427.
DR   PDB; 5JER; X-ray; 2.91 A; A/C/E/G=189-427.
DR   PDB; 6SIV; X-ray; 1.75 A; A=137-148.
DR   PDB; 6SJA; X-ray; 1.50 A; A=137-148.
DR   PDB; 7JFL; X-ray; 1.68 A; A/B=189-398.
DR   PDBsum; 1J2F; -.
DR   PDBsum; 1QWT; -.
DR   PDBsum; 1T2K; -.
DR   PDBsum; 1ZOQ; -.
DR   PDBsum; 2O61; -.
DR   PDBsum; 2O6G; -.
DR   PDBsum; 2PI0; -.
DR   PDBsum; 3A77; -.
DR   PDBsum; 3QU6; -.
DR   PDBsum; 5JEJ; -.
DR   PDBsum; 5JEK; -.
DR   PDBsum; 5JEL; -.
DR   PDBsum; 5JEM; -.
DR   PDBsum; 5JEO; -.
DR   PDBsum; 5JER; -.
DR   PDBsum; 6SIV; -.
DR   PDBsum; 6SJA; -.
DR   PDBsum; 7JFL; -.
DR   AlphaFoldDB; Q14653; -.
DR   SMR; Q14653; -.
DR   BioGRID; 109869; 144.
DR   CORUM; Q14653; -.
DR   DIP; DIP-41448N; -.
DR   ELM; Q14653; -.
DR   IntAct; Q14653; 71.
DR   MINT; Q14653; -.
DR   STRING; 9606.ENSP00000471896; -.
DR   BindingDB; Q14653; -.
DR   ChEMBL; CHEMBL4523293; -.
DR   iPTMnet; Q14653; -.
DR   PhosphoSitePlus; Q14653; -.
DR   BioMuta; IRF3; -.
DR   DMDM; 2497442; -.
DR   EPD; Q14653; -.
DR   jPOST; Q14653; -.
DR   MassIVE; Q14653; -.
DR   MaxQB; Q14653; -.
DR   PaxDb; 9606-ENSP00000471896; -.
DR   PeptideAtlas; Q14653; -.
DR   ProteomicsDB; 60091; -. [Q14653-1]
DR   ProteomicsDB; 60092; -. [Q14653-2]
DR   ProteomicsDB; 62791; -.
DR   Pumba; Q14653; -.
DR   Antibodypedia; 1283; 1659 antibodies from 47 providers.
DR   DNASU; 3661; -.
DR   Ensembl; ENST00000309877.11; ENSP00000310127.6; ENSG00000126456.16. [Q14653-1]
DR   Ensembl; ENST00000377139.8; ENSP00000366344.3; ENSG00000126456.16. [Q14653-1]
DR   Ensembl; ENST00000442265.2; ENSP00000400378.2; ENSG00000126456.16. [Q14653-5]
DR   Ensembl; ENST00000596765.5; ENSP00000470512.1; ENSG00000126456.16. [Q14653-3]
DR   Ensembl; ENST00000597198.5; ENSP00000469113.1; ENSG00000126456.16. [Q14653-1]
DR   Ensembl; ENST00000599223.5; ENSP00000471358.1; ENSG00000126456.16. [Q14653-2]
DR   Ensembl; ENST00000600022.5; ENSP00000472700.1; ENSG00000126456.16. [Q14653-3]
DR   Ensembl; ENST00000601291.5; ENSP00000471896.1; ENSG00000126456.16. [Q14653-4]
DR   GeneID; 3661; -.
DR   KEGG; hsa:3661; -.
DR   MANE-Select; ENST00000377139.8; ENSP00000366344.3; NM_001571.6; NP_001562.1.
DR   UCSC; uc002pot.3; human. [Q14653-1]
DR   AGR; HGNC:6118; -.
DR   CTD; 3661; -.
DR   DisGeNET; 3661; -.
DR   GeneCards; IRF3; -.
DR   HGNC; HGNC:6118; IRF3.
DR   HPA; ENSG00000126456; Low tissue specificity.
DR   MalaCards; IRF3; -.
DR   MIM; 603734; gene.
DR   MIM; 616532; phenotype.
DR   neXtProt; NX_Q14653; -.
DR   OpenTargets; ENSG00000126456; -.
DR   PharmGKB; PA29917; -.
DR   VEuPathDB; HostDB:ENSG00000126456; -.
DR   eggNOG; ENOG502QTRR; Eukaryota.
DR   GeneTree; ENSGT00940000160569; -.
DR   HOGENOM; CLU_031544_2_0_1; -.
DR   InParanoid; Q14653; -.
DR   OMA; DRGVMGY; -.
DR   OrthoDB; 3740806at2759; -.
DR   PhylomeDB; Q14653; -.
DR   TreeFam; TF328512; -.
DR   PathwayCommons; Q14653; -.
DR   Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
DR   Reactome; R-HSA-1606341; IRF3 mediated activation of type 1 IFN.
DR   Reactome; R-HSA-168928; DDX58/IFIH1-mediated induction of interferon-alpha/beta.
DR   Reactome; R-HSA-3134973; LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production.
DR   Reactome; R-HSA-3134975; Regulation of innate immune responses to cytosolic DNA.
DR   Reactome; R-HSA-3270619; IRF3-mediated induction of type I IFN.
DR   Reactome; R-HSA-877300; Interferon gamma signaling.
DR   Reactome; R-HSA-9013973; TICAM1-dependent activation of IRF3/IRF7.
DR   Reactome; R-HSA-909733; Interferon alpha/beta signaling.
DR   Reactome; R-HSA-918233; TRAF3-dependent IRF activation pathway.
DR   Reactome; R-HSA-933541; TRAF6 mediated IRF7 activation.
DR   Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR   Reactome; R-HSA-936964; Activation of IRF3, IRF7 mediated by TBK1, IKBKE.
DR   Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses.
DR   Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR   Reactome; R-HSA-9833109; Evasion by RSV of host interferon responses.
DR   SignaLink; Q14653; -.
DR   SIGNOR; Q14653; -.
DR   BioGRID-ORCS; 3661; 15 hits in 1188 CRISPR screens.
DR   ChiTaRS; IRF3; human.
DR   EvolutionaryTrace; Q14653; -.
DR   GeneWiki; IRF3; -.
DR   GenomeRNAi; 3661; -.
DR   Pharos; Q14653; Tbio.
DR   PRO; PR:Q14653; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; Q14653; Protein.
DR   Bgee; ENSG00000126456; Expressed in granulocyte and 181 other cell types or tissues.
DR   ExpressionAtlas; Q14653; baseline and differential.
DR   GO; GO:0000785; C:chromatin; IDA:UniProt.
DR   GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR   GO; GO:0003677; F:DNA binding; NAS:BHF-UCL.
DR   GO; GO:0001216; F:DNA-binding transcription activator activity; IDA:UniProt.
DR   GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IMP:NTNU_SB.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProt.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:ARUK-UCL.
DR   GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IEA:Ensembl.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:1990841; F:promoter-specific chromatin binding; IEA:Ensembl.
DR   GO; GO:0019904; F:protein domain specific binding; IPI:CAFA.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:ARUK-UCL.
DR   GO; GO:0043565; F:sequence-specific DNA binding; IDA:NTNU_SB.
DR   GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR   GO; GO:0140374; P:antiviral innate immune response; IDA:UniProt.
DR   GO; GO:0006915; P:apoptotic process; TAS:UniProtKB.
DR   GO; GO:0071360; P:cellular response to exogenous dsRNA; IEA:Ensembl.
DR   GO; GO:0098586; P:cellular response to virus; IDA:UniProtKB.
DR   GO; GO:0140896; P:cGAS/STING signaling pathway; TAS:FlyBase.
DR   GO; GO:0002753; P:cytoplasmic pattern recognition receptor signaling pathway; IDA:UniProt.
DR   GO; GO:0051607; P:defense response to virus; ISS:UniProtKB.
DR   GO; GO:0006974; P:DNA damage response; TAS:UniProtKB.
DR   GO; GO:0002376; P:immune system process; IBA:GO_Central.
DR   GO; GO:0045087; P:innate immune response; TAS:FlyBase.
DR   GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR   GO; GO:0071888; P:macrophage apoptotic process; TAS:UniProtKB.
DR   GO; GO:0039530; P:MDA-5 signaling pathway; TAS:UniProtKB.
DR   GO; GO:0009299; P:mRNA transcription; IDA:UniProt.
DR   GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IEA:Ensembl.
DR   GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; TAS:FlyBase.
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:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ARUK-UCL.
DR   GO; GO:0032481; P:positive regulation of type I interferon production; IDA: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; IDA: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:0023019; P:signal transduction involved in regulation of gene expression; TAS:FlyBase.
DR   GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProt.
DR   GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:0060337; P:type I interferon-mediated signaling pathway; IEA:Ensembl.
DR   CDD; cd00103; IRF; 1.
DR   DisProt; DP01614; -.
DR   Gene3D; 2.60.200.10; -; 1.
DR   Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1.
DR   IDEAL; IID00079; -.
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   PANTHER; PTHR11949; INTERFERON REGULATORY FACTOR; 1.
DR   PANTHER; PTHR11949:SF1; INTERFERON REGULATORY FACTOR 3; 1.
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; SSF49879; SMAD/FHA domain; 1.
DR   SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1.
DR   PROSITE; PS00601; IRF_1; 1.
DR   PROSITE; PS51507; IRF_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Activator; Alternative splicing;
KW   Antiviral defense; Cytoplasm; Disease variant; 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..427
FT                   /note="Interferon regulatory factor 3"
FT                   /id="PRO_0000154553"
FT   DNA_BIND        5..111
FT                   /note="IRF tryptophan pentad repeat"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00840"
FT   REGION          91..136
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          141..427
FT                   /note="Mediates interaction with ZDHHC11"
FT                   /evidence="ECO:0000269|PubMed:28331227"
FT   REGION          200..360
FT                   /note="Interaction with HERC5"
FT                   /evidence="ECO:0000269|PubMed:20308324"
FT   MOTIF           139..149
FT                   /note="Nuclear export signal"
FT   COMPBIAS        91..106
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        115..136
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            121..122
FT                   /note="Cleavage; by CASP3"
FT                   /evidence="ECO:0000269|PubMed:30878284"
FT   SITE            125..126
FT                   /note="Cleavage; by CASP3"
FT                   /evidence="ECO:0000269|PubMed:30878284"
FT   MOD_RES         3
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         14
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         75
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         97
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         123
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P70671"
FT   MOD_RES         175
FT                   /note="(Microbial infection) Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:24049179"
FT   MOD_RES         180
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         188
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         237
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         244
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         253
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         366
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P70671"
FT   MOD_RES         385
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:22394562"
FT   MOD_RES         386
FT                   /note="Diphosphoserine"
FT                   /evidence="ECO:0000269|PubMed:36603579"
FT   MOD_RES         386
FT                   /note="Phosphoserine; by TBK1"
FT                   /evidence="ECO:0000269|PubMed:22394562,
FT                   ECO:0000269|PubMed:23746807, ECO:0000269|PubMed:27302953,
FT                   ECO:0000269|PubMed:36603579"
FT   MOD_RES         396
FT                   /note="Phosphoserine; by IKKE and TBK1"
FT                   /evidence="ECO:0000269|PubMed:22394562,
FT                   ECO:0000269|PubMed:23478265, ECO:0000269|PubMed:27302953,
FT                   ECO:0000269|PubMed:36603579"
FT   MOD_RES         398
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         404
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   MOD_RES         427
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:23746807"
FT   DISULFID        267..289
FT                   /evidence="ECO:0000269|PubMed:14555995,
FT                   ECO:0000269|PubMed:14555996"
FT   CROSSLNK        193
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ISG15)"
FT                   /evidence="ECO:0000269|PubMed:20308324"
FT   CROSSLNK        360
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ISG15)"
FT                   /evidence="ECO:0000269|PubMed:20308324"
FT   CROSSLNK        366
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ISG15)"
FT                   /evidence="ECO:0000269|PubMed:20308324"
FT   VAR_SEQ         1..146
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|Ref.2"
FT                   /id="VSP_046911"
FT   VAR_SEQ         56..104
FT                   /note="AWAEATGAYVPGRDKPDLPTWKRNFRSALNRKEGLRLAEDRSKDPHDPH ->
FT                   ELGTFPSQTPLRTPMVEAVLLIPRKTFWMSYWVTWCWPHSQIRDPQAWL (in
FT                   isoform 5)"
FT                   /evidence="ECO:0000303|Ref.2"
FT                   /id="VSP_047690"
FT   VAR_SEQ         105..427
FT                   /note="Missing (in isoform 5)"
FT                   /evidence="ECO:0000303|Ref.2"
FT                   /id="VSP_047691"
FT   VAR_SEQ         201..327
FT                   /note="Missing (in isoform 2 and isoform 3)"
FT                   /evidence="ECO:0000303|Ref.2"
FT                   /id="VSP_043319"
FT   VAR_SEQ         328..427
FT                   /note="DLITFTEGSGRSPRYALWFCVGESWPQDQPWTKRLVMVKVVPTCLRALVEMA
FT                   RVGGASSLENTVDLHISNSHPLSLTSDQYKAYLQDLVEGMDFQGPGES -> GSWAPRS
FT                   DYLHGRKRTLTTLCPLVLCGGVMAPGPAVDQEARDGQGCAHVPQGLGRNGPGRGCLLPG
FT                   EYCGPAHFQQPPTLPHLRPVQGLPAGLGGGHGFPGPWGELSPRSSWCASNPPVPHHLNQ
FT                   (in isoform 4)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_046912"
FT   VARIANT         49
FT                   /note="Missing (decreased IFNB induction upon Sendai virus
FT                   infection)"
FT                   /evidence="ECO:0000269|PubMed:32972995"
FT                   /id="VAR_084069"
FT   VARIANT         96
FT                   /note="R -> Q (in dbSNP:rs968457)"
FT                   /id="VAR_011901"
FT   VARIANT         107
FT                   /note="Y -> F (in dbSNP:rs34745118)"
FT                   /id="VAR_049643"
FT   VARIANT         145..200
FT                   /note="Missing (decreased IFNB induction upon Sendai virus
FT                   infection)"
FT                   /evidence="ECO:0000269|PubMed:32972995"
FT                   /id="VAR_084070"
FT   VARIANT         146
FT                   /note="N -> K (decreased IFNB induction upon Sendai virus
FT                   infection)"
FT                   /evidence="ECO:0000269|PubMed:32972995"
FT                   /id="VAR_084071"
FT   VARIANT         227
FT                   /note="R -> Q (no effect on IFNB induction upon Sendai
FT                   virus infection)"
FT                   /evidence="ECO:0000269|PubMed:32972995"
FT                   /id="VAR_084072"
FT   VARIANT         285
FT                   /note="R -> Q (in IIAE7; loss of viral infection-induced
FT                   phosphorylation at S-386; loss of viral infection-induced
FT                   homodimerization; loss of viral infection-induced
FT                   transcription factor activity; unable to activate
FT                   interferon transcription in response to viral infection;
FT                   decreased IFNB induction upon Sendai virus infection;
FT                   dbSNP:rs750526659)"
FT                   /evidence="ECO:0000269|PubMed:26216125,
FT                   ECO:0000269|PubMed:32972995"
FT                   /id="VAR_075805"
FT   VARIANT         377
FT                   /note="E -> K (in dbSNP:rs1049486)"
FT                   /id="VAR_011902"
FT   VARIANT         401
FT                   /note="L -> V (no effect on IFNB induction upon Sendai
FT                   virus infection)"
FT                   /evidence="ECO:0000269|PubMed:32972995"
FT                   /id="VAR_084073"
FT   VARIANT         427
FT                   /note="S -> T (in dbSNP:rs7251)"
FT                   /evidence="ECO:0000269|PubMed:14702039, ECO:0000269|Ref.5"
FT                   /id="VAR_011903"
FT   MUTAGEN         77..78
FT                   /note="KR->NG: Abolishes nuclear localization."
FT                   /evidence="ECO:0000269|PubMed:10805757"
FT   MUTAGEN         86..87
FT                   /note="RK->LQ: No effect on subcellular localization."
FT                   /evidence="ECO:0000269|PubMed:10805757"
FT   MUTAGEN         116
FT                   /note="D->A: Does not affect cleavage by CASP3."
FT                   /evidence="ECO:0000269|PubMed:30878284"
FT   MUTAGEN         121..125
FT                   /note="DTSPD->ATSPA: Abolished cleavage by CASP3."
FT                   /evidence="ECO:0000269|PubMed:30878284"
FT   MUTAGEN         139..140
FT                   /note="IL->MM: Abolishes nuclear export."
FT                   /evidence="ECO:0000269|PubMed:10805757"
FT   MUTAGEN         193
FT                   /note="K->R: Highly diminished ISGylation; when associated
FT                   with R-360 and R-366."
FT                   /evidence="ECO:0000269|PubMed:20308324"
FT   MUTAGEN         285
FT                   /note="R->S: Abolished interaction with STING1, MAVS or
FT                   TICAM1."
FT                   /evidence="ECO:0000269|PubMed:27302953"
FT   MUTAGEN         288
FT                   /note="H->S: Decreased interaction with TICAM1."
FT                   /evidence="ECO:0000269|PubMed:27302953"
FT   MUTAGEN         290
FT                   /note="H->S: Decreased interaction with TICAM1."
FT                   /evidence="ECO:0000269|PubMed:27302953"
FT   MUTAGEN         313
FT                   /note="K->S: Abolished interaction with STING1, MAVS or
FT                   TICAM1."
FT                   /evidence="ECO:0000269|PubMed:27302953"
FT   MUTAGEN         360
FT                   /note="K->R: Highly diminished ISGylation; when associated
FT                   with R-193 and R-366."
FT                   /evidence="ECO:0000269|PubMed:20308324"
FT   MUTAGEN         366
FT                   /note="K->R: Highly diminished ISGylation; when associated
FT                   with R-193 and R-360."
FT                   /evidence="ECO:0000269|PubMed:20308324"
FT   MUTAGEN         385..386
FT                   /note="SS->AA: Complete loss of viral infection induced
FT                   phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:9566918"
FT   MUTAGEN         385
FT                   /note="S->A,D,E: Complete loss of viral infection induced
FT                   phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:10920266,
FT                   ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:25636800"
FT   MUTAGEN         386
FT                   /note="S->A: Complete loss of viral infection induced
FT                   phosphorylation. Abolished pyrophosphorylation."
FT                   /evidence="ECO:0000269|PubMed:10920266,
FT                   ECO:0000269|PubMed:22394562, ECO:0000269|PubMed:23746807,
FT                   ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:36603579"
FT   MUTAGEN         386
FT                   /note="S->E: Phosphomimetic mutant; interacts with CREBBP;
FT                   when associated with E-396."
FT                   /evidence="ECO:0000269|PubMed:27302953"
FT   MUTAGEN         390
FT                   /note="T->A: Does not affect pyrophosphorylation."
FT                   /evidence="ECO:0000269|PubMed:36603579"
FT   MUTAGEN         396..405
FT                   /note="SNSHPLSLTS->ANAHPLALAA: Complete loss of viral
FT                   infection induced phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:9566918"
FT   MUTAGEN         396..405
FT                   /note="SNSHPLSLTS->DNDHPLDLDD: Acts as a constitutively
FT                   activated IRF3."
FT                   /evidence="ECO:0000269|PubMed:9566918"
FT   MUTAGEN         396..398
FT                   /note="SNS->ANA: Complete loss of viral infection induced
FT                   phosphorylation."
FT   MUTAGEN         396
FT                   /note="S->E: Phosphomimetic mutant; interacts with CREBBP;
FT                   when associated with E-386."
FT                   /evidence="ECO:0000269|PubMed:27302953"
FT   MUTAGEN         402..405
FT                   /note="SLTS->ALAA: Complete loss of viral infection induced
FT                   phosphorylation."
FT   CONFLICT        196
FT                   /note="L -> F (in Ref. 3; BAG37040)"
FT                   /evidence="ECO:0000305"
FT   HELIX           8..18
FT                   /evidence="ECO:0007829|PDB:3QU6"
FT   STRAND          25..27
FT                   /evidence="ECO:0007829|PDB:2O61"
FT   STRAND          28..31
FT                   /evidence="ECO:0007829|PDB:2PI0"
FT   STRAND          33..37
FT                   /evidence="ECO:0007829|PDB:3QU6"
FT   STRAND          41..45
FT                   /evidence="ECO:0007829|PDB:2O6G"
FT   HELIX           49..51
FT                   /evidence="ECO:0007829|PDB:2PI0"
FT   HELIX           53..60
FT                   /evidence="ECO:0007829|PDB:3QU6"
FT   STRAND          66..69
FT                   /evidence="ECO:0007829|PDB:2O61"
FT   HELIX           73..85
FT                   /evidence="ECO:0007829|PDB:3QU6"
FT   STRAND          90..96
FT                   /evidence="ECO:0007829|PDB:3QU6"
FT   STRAND          100..102
FT                   /evidence="ECO:0007829|PDB:3QU6"
FT   STRAND          104..109
FT                   /evidence="ECO:0007829|PDB:3QU6"
FT   HELIX           137..143
FT                   /evidence="ECO:0007829|PDB:6SJA"
FT   HELIX           191..196
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          204..210
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          213..220
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          226..229
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          238..244
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   HELIX           248..250
FT                   /evidence="ECO:0007829|PDB:7JFL"
FT   STRAND          252..254
FT                   /evidence="ECO:0007829|PDB:5JEJ"
FT   HELIX           255..266
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   TURN            267..270
FT                   /evidence="ECO:0007829|PDB:1ZOQ"
FT   STRAND          272..277
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          280..285
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          287..289
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          291..297
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          304..306
FT                   /evidence="ECO:0007829|PDB:5JEO"
FT   STRAND          308..310
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          313..315
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          317..321
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   HELIX           322..333
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          343..350
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          354..356
FT                   /evidence="ECO:0007829|PDB:7JFL"
FT   HELIX           358..360
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          361..369
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   HELIX           370..383
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          384..391
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   STRAND          395..397
FT                   /evidence="ECO:0007829|PDB:5JER"
FT   STRAND          401..404
FT                   /evidence="ECO:0007829|PDB:5JEL"
FT   HELIX           405..417
FT                   /evidence="ECO:0007829|PDB:5JEL"
SQ   SEQUENCE   427 AA;  47219 MW;  F536676FA78B0110 CRC64;
     MGTPKPRILP WLVSQLDLGQ LEGVAWVNKS RTRFRIPWKH GLRQDAQQED FGIFQAWAEA
     TGAYVPGRDK PDLPTWKRNF RSALNRKEGL RLAEDRSKDP HDPHKIYEFV NSGVGDFSQP
     DTSPDTNGGG STSDTQEDIL DELLGNMVLA PLPDPGPPSL AVAPEPCPQP LRSPSLDNPT
     PFPNLGPSEN PLKRLLVPGE EWEFEVTAFY RGRQVFQQTI SCPEGLRLVG SEVGDRTLPG
     WPVTLPDPGM SLTDRGVMSY VRHVLSCLGG GLALWRAGQW LWAQRLGHCH TYWAVSEELL
     PNSGHGPDGE VPKDKEGGVF DLGPFIVDLI TFTEGSGRSP RYALWFCVGE SWPQDQPWTK
     RLVMVKVVPT CLRALVEMAR VGGASSLENT VDLHISNSHP LSLTSDQYKA YLQDLVEGMD
     FQGPGES
//