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 27-MAR-2024, entry version 217.
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:8524823,
CC PubMed:22394562, PubMed:25636800, PubMed:27302953, PubMed:24049179,
CC PubMed:31340999, PubMed:36603579). Regulates the transcription of type
CC I 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:8524823, PubMed:11846977, PubMed:16846591,
CC PubMed:16979567, PubMed:20049431, PubMed:36603579, PubMed:32972995).
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:36603579, PubMed:27302953).
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:28331227,
CC PubMed:25636800, PubMed:27302953). 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: 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; 143.
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; 1663 antibodies from 46 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 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 Genevisible; Q14653; HS.
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: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: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: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: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; Activator; Alternative splicing; Antiviral defense;
KW 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 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
//