Full text data of IRF3
IRF3
[Confidence: low (only semi-automatic identification from reviews)]
Interferon regulatory factor 3; IRF-3
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Interferon regulatory factor 3; IRF-3
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q14653
ID IRF3_HUMAN Reviewed; 427 AA.
AC Q14653; A8K7L2; Q5FBY1; Q5FBY2; Q5FBY4; Q7Z5G6;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1997, sequence version 1.
DT 22-JAN-2014, entry version 133.
DE RecName: Full=Interferon regulatory factor 3;
DE Short=IRF-3;
GN Name=IRF3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
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
RT that 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
RP 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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA 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.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA 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
RT project: 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;
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
RT proteasome-mediated degradation.";
RL Mol. Cell. Biol. 18:2986-2996(1998).
RN [9]
RP MUTAGENESIS OF SER-385 AND SER-386.
RX PubMed=10920266;
RA Suhara W., Yoneyama M., Iwamura T., Yoshimura S., Tamura K.,
RA Namiki H., Aimoto S., Fujita T.;
RT "Analyses of virus-induced homomeric and heteromeric protein
RT associations 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
RP AND 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
RT factor 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.,
RA Julkunen I., 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.
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
RT require double-stranded RNA-dependent protein kinase R or Ikappa B
RT kinase but is blocked by Vaccinia virus E3L protein.";
RL J. Biol. Chem. 276:8951-8957(2001).
RN [13]
RP INTERACTION WITH HHV-8 PROTEIN VIRF1.
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;
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
RT preferentially activates the IFN-beta promoter in the Toll-like
RT receptor signaling.";
RL J. Immunol. 169:6668-6672(2002).
RN [16]
RP INTERACTION WITH ROTAVIRUS A NSP1.
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
RT 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
RT adapters TRAM and TRIF.";
RL J. Exp. Med. 198:1043-1055(2003).
RN [18]
RP ERRATUM.
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.,
RA 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
RT and 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
RT and 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.
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
RT RBCK1-mediated degradation of IRF3.";
RL Cell Res. 18:1096-1104(2008).
RN [27]
RP INTERACTION WITH TRIM21, AND POLYUBIQUITINATION.
RX PubMed=18641315;
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
RT IRF3.";
RL J. Immunol. 181:1780-1786(2008).
RN [28]
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
RT factor family.";
RL Cancer Immunol. Immunother. 59:489-510(2010).
RN [29]
RP ISGYLATION AT LYS-193; LYS-360 AND LYS-366, MUTAGENESIS OF LYS-193;
RP LYS-360 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.,
RA Wang C.;
RT "Positive regulation of interferon regulatory factor 3 activation by
RT Herc5 via ISG15 modification.";
RL Mol. Cell. Biol. 30:2424-2436(2010).
RN [30]
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 [31]
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
RT virus-induced phosphoactivation.";
RL Nat. Struct. Biol. 10:913-921(2003).
RN [32]
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-
RT beta enhancer.";
RL EMBO J. 23:4384-4393(2004).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 173-394.
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.,
RA Lin K.;
RT "Crystal structure of IRF-3 in complex with CBP.";
RL Structure 13:1269-1277(2005).
CC -!- FUNCTION: Key transcriptional regulator of type I interferon
CC (IFN)-dependent immune responses and plays a critical role in the
CC innate immune response against DNA and RNA viruses. Regulates the
CC transcription of type I IFN genes (IFN-alpha and IFN-beta) and
CC IFN-stimulated genes (ISG) by binding to an interferon-stimulated
CC response element (ISRE) in their promoters. Acts as a more potent
CC activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA)
CC gene and plays a critical role in both the early and late phases
CC of the IFNA/B gene induction. Found in an inactive form in the
CC cytoplasm of uninfected cells and following viral infection,
CC double-stranded RNA (dsRNA), or toll-like receptor (TLR)
CC signaling, becomes phosphorylated by IKBKE and TBK1 kinases. This
CC induces a conformational change, leading to its dimerization and
CC nuclear localization and association with CREB binding protein
CC (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which
CC activates the transcription of the type I IFN and ISG genes. Can
CC activate distinct gene expression programs in macrophages and can
CC induce significant apoptosis in primary macrophages.
CC -!- ENZYME REGULATION: In the absence of viral infection, maintained
CC as a monomer in an autoinhibited state and phosphorylation
CC disrupts this autoinhibition leading to the liberation of the DNA-
CC binding and dimerization activities and its nuclear localization
CC where it can activate type I IFN and ISG genes.
CC -!- SUBUNIT: Monomer. Homodimer; phosphorylation-induced. Heterodimer
CC with IRF7. Interacts with CREBBP. May interact with MAVS.
CC Interacts with IKBKE and TBK1. Interacts with TICAM1 and TICAM2.
CC Interacts with rotavirus A NSP1 (via C-terminus); this interaction
CC leads to the proteasome-dependent degradation of IRF3. Interacts
CC with RBCK1. Interacts with TRIM21. Interacts with HERC5. Interacts
CC with herpes virus 8/HHV-8 protein vIRF-1.
CC -!- INTERACTION:
CC Self; NbExp=9; IntAct=EBI-2650369, EBI-2650369;
CC Q92793:CREBBP; NbExp=4; IntAct=EBI-2650369, EBI-81215;
CC Q9Y3R0:GRIP1; NbExp=2; IntAct=EBI-2650369, EBI-5349621;
CC Q9Y5Q3:MAFB; NbExp=4; IntAct=EBI-2650369, EBI-3649340;
CC P06400:RB1; NbExp=2; IntAct=EBI-2650369, EBI-491274;
CC P28749:RBL1; NbExp=2; IntAct=EBI-2650369, EBI-971402;
CC O43765:SGTA; NbExp=3; IntAct=EBI-2650369, EBI-347996;
CC Q9UHD2:TBK1; NbExp=7; IntAct=EBI-2650369, EBI-356402;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Shuttles between
CC cytoplasmic and nuclear compartments, with export being the
CC prevailing effect. When activated, IRF3 interaction with CREBBP
CC prevents its export to the cytoplasm.
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 Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q14653-5; Sequence=VSP_047690, VSP_047691;
CC -!- TISSUE SPECIFICITY: Expressed constitutively in a variety of
CC tissues.
CC -!- PTM: Constitutively phosphorylated on many serines residues. C-
CC terminal serine/threonine cluster is phosphorylated in response of
CC induction by IKBKE and TBK1. Ser-385 and Ser-386 may be
CC specifically phosphorylated in response to induction. An alternate
CC model propose that the five serine/threonine residues between 396
CC and 405 are phosphorylated in response to a viral infection.
CC Phosphorylation, and subsequent activation of IRF3 is inhibited by
CC vaccinia virus protein E3.
CC -!- PTM: Ubiquitinated; ubiquitination involves RBCK1 leading to
CC proteasomal degradation. Polyubiquitinated; ubiquitination
CC involves TRIM21 leading to proteasomal degradation.
CC -!- PTM: ISGylated by HERC5 resulting in sustained IRF3 activation and
CC in the inhibition of IRF3 ubiquitination by disrupting PIN1
CC binding. The phosphorylation state of IRF3 does not alter
CC ISGylation.
CC -!- SIMILARITY: Belongs to the IRF family.
CC -!- SIMILARITY: Contains 1 IRF tryptophan pentad repeat DNA-binding
CC domain.
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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; 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 RefSeq; NP_001184051.1; NM_001197122.1.
DR RefSeq; NP_001184052.1; NM_001197123.1.
DR RefSeq; NP_001184053.1; NM_001197124.1.
DR RefSeq; NP_001184054.1; NM_001197125.1.
DR RefSeq; NP_001184055.1; NM_001197126.1.
DR RefSeq; NP_001184056.1; NM_001197127.1.
DR RefSeq; NP_001184057.1; NM_001197128.1.
DR RefSeq; NP_001562.1; NM_001571.5.
DR UniGene; Hs.289052; -.
DR UniGene; Hs.731922; -.
DR UniGene; Hs.75254; -.
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=4-111.
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 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 ProteinModelPortal; Q14653; -.
DR SMR; Q14653; 1-112, 189-427.
DR DIP; DIP-41448N; -.
DR IntAct; Q14653; 20.
DR MINT; MINT-253351; -.
DR STRING; 9606.ENSP00000310127; -.
DR PhosphoSite; Q14653; -.
DR DMDM; 2497442; -.
DR PaxDb; Q14653; -.
DR PeptideAtlas; Q14653; -.
DR PRIDE; Q14653; -.
DR DNASU; 3661; -.
DR Ensembl; ENST00000309877; ENSP00000310127; ENSG00000126456.
DR Ensembl; ENST00000377135; ENSP00000366339; ENSG00000126456.
DR Ensembl; ENST00000377139; ENSP00000366344; ENSG00000126456.
DR Ensembl; ENST00000442265; ENSP00000400378; ENSG00000126456.
DR Ensembl; ENST00000596765; ENSP00000470512; ENSG00000126456.
DR Ensembl; ENST00000597198; ENSP00000469113; ENSG00000126456.
DR Ensembl; ENST00000599223; ENSP00000471358; ENSG00000126456.
DR Ensembl; ENST00000600022; ENSP00000472700; ENSG00000126456.
DR Ensembl; ENST00000601291; ENSP00000471896; ENSG00000126456.
DR GeneID; 3661; -.
DR KEGG; hsa:3661; -.
DR UCSC; uc002pou.3; human.
DR CTD; 3661; -.
DR GeneCards; GC19M050162; -.
DR HGNC; HGNC:6118; IRF3.
DR HPA; CAB013018; -.
DR HPA; HPA004895; -.
DR MIM; 603734; gene.
DR neXtProt; NX_Q14653; -.
DR PharmGKB; PA29917; -.
DR eggNOG; NOG42868; -.
DR HOGENOM; HOG000033705; -.
DR HOVERGEN; HBG105601; -.
DR KO; K05411; -.
DR OMA; CHTYWAV; -.
DR OrthoDB; EOG7CCBR1; -.
DR PhylomeDB; Q14653; -.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; IRF3; human.
DR EvolutionaryTrace; Q14653; -.
DR GeneWiki; IRF3; -.
DR GenomeRNAi; 3661; -.
DR NextBio; 14319; -.
DR PRO; PR:Q14653; -.
DR ArrayExpress; Q14653; -.
DR Bgee; Q14653; -.
DR CleanEx; HS_IRF3; -.
DR Genevestigator; Q14653; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0003677; F:DNA binding; NAS:BHF-UCL.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; IEA:InterPro.
DR GO; GO:0003712; F:transcription cofactor activity; TAS:ProtInc.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; TAS:UniProtKB.
DR GO; GO:0071359; P:cellular response to dsRNA; IEA:Ensembl.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
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:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0050689; P:negative regulation of defense response to virus by host; IEA:Ensembl.
DR GO; GO:0045358; P:negative regulation of interferon-beta biosynthetic process; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0050715; P:positive regulation of cytokine secretion; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; 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:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0006366; P:transcription from RNA polymerase II promoter; TAS:ProtInc.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045351; P:type I interferon biosynthetic process; IEA:Ensembl.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 2.60.200.10; -; 1.
DR InterPro; IPR019817; Interferon_reg_fac_CS.
DR InterPro; IPR001346; Interferon_reg_fact_DNA-bd_dom.
DR InterPro; IPR019471; Interferon_reg_factor-3.
DR InterPro; IPR017855; SMAD_dom-like.
DR InterPro; IPR008984; SMAD_FHA_domain.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00605; IRF; 1.
DR Pfam; PF10401; IRF-3; 1.
DR PRINTS; PR00267; INTFRNREGFCT.
DR SMART; SM00348; IRF; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR PROSITE; PS00601; IRF_1; 1.
DR PROSITE; PS51507; IRF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Antiviral defense;
KW Complete proteome; Cytoplasm; Disulfide bond; DNA-binding;
KW Host-virus interaction; Immunity; Innate immunity; Isopeptide bond;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1 427 Interferon regulatory factor 3.
FT /FTId=PRO_0000154553.
FT DNA_BIND 5 111 IRF tryptophan pentad repeat.
FT REGION 200 360 Involved in HERC5 binding.
FT MOTIF 139 149 Nuclear export signal.
FT COMPBIAS 151 191 Pro-rich.
FT DISULFID 267 289
FT CROSSLNK 193 193 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT CROSSLNK 360 360 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT CROSSLNK 366 366 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT VAR_SEQ 1 146 Missing (in isoform 3).
FT /FTId=VSP_046911.
FT VAR_SEQ 56 104 AWAEATGAYVPGRDKPDLPTWKRNFRSALNRKEGLRLAEDR
FT SKDPHDPH -> ELGTFPSQTPLRTPMVEAVLLIPRKTFWM
FT SYWVTWCWPHSQIRDPQAWL (in isoform 5).
FT /FTId=VSP_047690.
FT VAR_SEQ 105 427 Missing (in isoform 5).
FT /FTId=VSP_047691.
FT VAR_SEQ 201 327 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_043319.
FT VAR_SEQ 328 427 DLITFTEGSGRSPRYALWFCVGESWPQDQPWTKRLVMVKVV
FT PTCLRALVEMARVGGASSLENTVDLHISNSHPLSLTSDQYK
FT AYLQDLVEGMDFQGPGES -> GSWAPRSDYLHGRKRTLTT
FT LCPLVLCGGVMAPGPAVDQEARDGQGCAHVPQGLGRNGPGR
FT GCLLPGEYCGPAHFQQPPTLPHLRPVQGLPAGLGGGHGFPG
FT PWGELSPRSSWCASNPPVPHHLNQ (in isoform 4).
FT /FTId=VSP_046912.
FT VARIANT 96 96 R -> Q (in dbSNP:rs968457).
FT /FTId=VAR_011901.
FT VARIANT 107 107 Y -> F (in dbSNP:rs34745118).
FT /FTId=VAR_049643.
FT VARIANT 377 377 E -> K (in dbSNP:rs1049486).
FT /FTId=VAR_011902.
FT VARIANT 427 427 S -> T (in dbSNP:rs7251).
FT /FTId=VAR_011903.
FT MUTAGEN 77 78 KR->NG: Abolishes nuclear localization.
FT MUTAGEN 86 87 RK->LQ: No effect on subcellular
FT localization.
FT MUTAGEN 139 140 IL->MM: Abolishes nuclear export.
FT MUTAGEN 193 193 K->R: Highly diminished ISGylation; when
FT associated with R-360 and R-366.
FT MUTAGEN 360 360 K->R: Highly diminished ISGylation; when
FT associated with R-193 and R-366.
FT MUTAGEN 366 366 K->R: Highly diminished ISGylation; when
FT associated with R-193 and R-360.
FT MUTAGEN 385 386 SS->AA: Complete loss of viral infection
FT induced phosphorylation.
FT MUTAGEN 385 385 S->A,D,E: Complete loss of viral
FT infection induced phosphorylation.
FT MUTAGEN 386 386 S->A,D,E: Complete loss of viral
FT infection induced phosphorylation.
FT MUTAGEN 396 405 SNSHPLSLTS->ANAHPLALAA: Complete loss of
FT viral infection induced phosphorylation.
FT MUTAGEN 396 405 SNSHPLSLTS->DNDHPLDLDD: Acts as a
FT constitutively activated IRF3.
FT MUTAGEN 396 398 SNS->ANA: Complete loss of viral
FT infection induced phosphorylation.
FT MUTAGEN 402 405 SLTS->ALAA: Complete loss of viral
FT infection induced phosphorylation.
FT HELIX 8 18
FT STRAND 25 27
FT STRAND 28 31
FT STRAND 33 37
FT STRAND 41 45
FT HELIX 49 51
FT HELIX 53 60
FT STRAND 66 69
FT HELIX 73 85
FT STRAND 90 96
FT STRAND 100 102
FT STRAND 104 109
FT HELIX 191 195
FT STRAND 202 210
FT STRAND 213 221
FT STRAND 226 229
FT STRAND 239 244
FT HELIX 248 250
FT HELIX 255 267
FT STRAND 272 277
FT STRAND 280 285
FT STRAND 287 289
FT STRAND 291 296
FT STRAND 308 310
FT STRAND 313 315
FT STRAND 317 321
FT HELIX 322 333
FT STRAND 343 348
FT STRAND 354 356
FT HELIX 357 360
FT STRAND 363 369
FT HELIX 370 383
FT STRAND 389 391
FT STRAND 401 403
FT HELIX 405 416
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
//
ID IRF3_HUMAN Reviewed; 427 AA.
AC Q14653; A8K7L2; Q5FBY1; Q5FBY2; Q5FBY4; Q7Z5G6;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1997, sequence version 1.
DT 22-JAN-2014, entry version 133.
DE RecName: Full=Interferon regulatory factor 3;
DE Short=IRF-3;
GN Name=IRF3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
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
RT that 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
RP 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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA 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.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA 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
RT project: 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;
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
RT proteasome-mediated degradation.";
RL Mol. Cell. Biol. 18:2986-2996(1998).
RN [9]
RP MUTAGENESIS OF SER-385 AND SER-386.
RX PubMed=10920266;
RA Suhara W., Yoneyama M., Iwamura T., Yoshimura S., Tamura K.,
RA Namiki H., Aimoto S., Fujita T.;
RT "Analyses of virus-induced homomeric and heteromeric protein
RT associations 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
RP AND 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
RT factor 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.,
RA Julkunen I., 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.
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
RT require double-stranded RNA-dependent protein kinase R or Ikappa B
RT kinase but is blocked by Vaccinia virus E3L protein.";
RL J. Biol. Chem. 276:8951-8957(2001).
RN [13]
RP INTERACTION WITH HHV-8 PROTEIN VIRF1.
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;
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
RT preferentially activates the IFN-beta promoter in the Toll-like
RT receptor signaling.";
RL J. Immunol. 169:6668-6672(2002).
RN [16]
RP INTERACTION WITH ROTAVIRUS A NSP1.
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
RT 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
RT adapters TRAM and TRIF.";
RL J. Exp. Med. 198:1043-1055(2003).
RN [18]
RP ERRATUM.
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.,
RA 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
RT and 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
RT and 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.
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
RT RBCK1-mediated degradation of IRF3.";
RL Cell Res. 18:1096-1104(2008).
RN [27]
RP INTERACTION WITH TRIM21, AND POLYUBIQUITINATION.
RX PubMed=18641315;
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
RT IRF3.";
RL J. Immunol. 181:1780-1786(2008).
RN [28]
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
RT factor family.";
RL Cancer Immunol. Immunother. 59:489-510(2010).
RN [29]
RP ISGYLATION AT LYS-193; LYS-360 AND LYS-366, MUTAGENESIS OF LYS-193;
RP LYS-360 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.,
RA Wang C.;
RT "Positive regulation of interferon regulatory factor 3 activation by
RT Herc5 via ISG15 modification.";
RL Mol. Cell. Biol. 30:2424-2436(2010).
RN [30]
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 [31]
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
RT virus-induced phosphoactivation.";
RL Nat. Struct. Biol. 10:913-921(2003).
RN [32]
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-
RT beta enhancer.";
RL EMBO J. 23:4384-4393(2004).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 173-394.
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.,
RA Lin K.;
RT "Crystal structure of IRF-3 in complex with CBP.";
RL Structure 13:1269-1277(2005).
CC -!- FUNCTION: Key transcriptional regulator of type I interferon
CC (IFN)-dependent immune responses and plays a critical role in the
CC innate immune response against DNA and RNA viruses. Regulates the
CC transcription of type I IFN genes (IFN-alpha and IFN-beta) and
CC IFN-stimulated genes (ISG) by binding to an interferon-stimulated
CC response element (ISRE) in their promoters. Acts as a more potent
CC activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA)
CC gene and plays a critical role in both the early and late phases
CC of the IFNA/B gene induction. Found in an inactive form in the
CC cytoplasm of uninfected cells and following viral infection,
CC double-stranded RNA (dsRNA), or toll-like receptor (TLR)
CC signaling, becomes phosphorylated by IKBKE and TBK1 kinases. This
CC induces a conformational change, leading to its dimerization and
CC nuclear localization and association with CREB binding protein
CC (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which
CC activates the transcription of the type I IFN and ISG genes. Can
CC activate distinct gene expression programs in macrophages and can
CC induce significant apoptosis in primary macrophages.
CC -!- ENZYME REGULATION: In the absence of viral infection, maintained
CC as a monomer in an autoinhibited state and phosphorylation
CC disrupts this autoinhibition leading to the liberation of the DNA-
CC binding and dimerization activities and its nuclear localization
CC where it can activate type I IFN and ISG genes.
CC -!- SUBUNIT: Monomer. Homodimer; phosphorylation-induced. Heterodimer
CC with IRF7. Interacts with CREBBP. May interact with MAVS.
CC Interacts with IKBKE and TBK1. Interacts with TICAM1 and TICAM2.
CC Interacts with rotavirus A NSP1 (via C-terminus); this interaction
CC leads to the proteasome-dependent degradation of IRF3. Interacts
CC with RBCK1. Interacts with TRIM21. Interacts with HERC5. Interacts
CC with herpes virus 8/HHV-8 protein vIRF-1.
CC -!- INTERACTION:
CC Self; NbExp=9; IntAct=EBI-2650369, EBI-2650369;
CC Q92793:CREBBP; NbExp=4; IntAct=EBI-2650369, EBI-81215;
CC Q9Y3R0:GRIP1; NbExp=2; IntAct=EBI-2650369, EBI-5349621;
CC Q9Y5Q3:MAFB; NbExp=4; IntAct=EBI-2650369, EBI-3649340;
CC P06400:RB1; NbExp=2; IntAct=EBI-2650369, EBI-491274;
CC P28749:RBL1; NbExp=2; IntAct=EBI-2650369, EBI-971402;
CC O43765:SGTA; NbExp=3; IntAct=EBI-2650369, EBI-347996;
CC Q9UHD2:TBK1; NbExp=7; IntAct=EBI-2650369, EBI-356402;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Shuttles between
CC cytoplasmic and nuclear compartments, with export being the
CC prevailing effect. When activated, IRF3 interaction with CREBBP
CC prevents its export to the cytoplasm.
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 Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q14653-5; Sequence=VSP_047690, VSP_047691;
CC -!- TISSUE SPECIFICITY: Expressed constitutively in a variety of
CC tissues.
CC -!- PTM: Constitutively phosphorylated on many serines residues. C-
CC terminal serine/threonine cluster is phosphorylated in response of
CC induction by IKBKE and TBK1. Ser-385 and Ser-386 may be
CC specifically phosphorylated in response to induction. An alternate
CC model propose that the five serine/threonine residues between 396
CC and 405 are phosphorylated in response to a viral infection.
CC Phosphorylation, and subsequent activation of IRF3 is inhibited by
CC vaccinia virus protein E3.
CC -!- PTM: Ubiquitinated; ubiquitination involves RBCK1 leading to
CC proteasomal degradation. Polyubiquitinated; ubiquitination
CC involves TRIM21 leading to proteasomal degradation.
CC -!- PTM: ISGylated by HERC5 resulting in sustained IRF3 activation and
CC in the inhibition of IRF3 ubiquitination by disrupting PIN1
CC binding. The phosphorylation state of IRF3 does not alter
CC ISGylation.
CC -!- SIMILARITY: Belongs to the IRF family.
CC -!- SIMILARITY: Contains 1 IRF tryptophan pentad repeat DNA-binding
CC domain.
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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; 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 RefSeq; NP_001184051.1; NM_001197122.1.
DR RefSeq; NP_001184052.1; NM_001197123.1.
DR RefSeq; NP_001184053.1; NM_001197124.1.
DR RefSeq; NP_001184054.1; NM_001197125.1.
DR RefSeq; NP_001184055.1; NM_001197126.1.
DR RefSeq; NP_001184056.1; NM_001197127.1.
DR RefSeq; NP_001184057.1; NM_001197128.1.
DR RefSeq; NP_001562.1; NM_001571.5.
DR UniGene; Hs.289052; -.
DR UniGene; Hs.731922; -.
DR UniGene; Hs.75254; -.
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=4-111.
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 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 ProteinModelPortal; Q14653; -.
DR SMR; Q14653; 1-112, 189-427.
DR DIP; DIP-41448N; -.
DR IntAct; Q14653; 20.
DR MINT; MINT-253351; -.
DR STRING; 9606.ENSP00000310127; -.
DR PhosphoSite; Q14653; -.
DR DMDM; 2497442; -.
DR PaxDb; Q14653; -.
DR PeptideAtlas; Q14653; -.
DR PRIDE; Q14653; -.
DR DNASU; 3661; -.
DR Ensembl; ENST00000309877; ENSP00000310127; ENSG00000126456.
DR Ensembl; ENST00000377135; ENSP00000366339; ENSG00000126456.
DR Ensembl; ENST00000377139; ENSP00000366344; ENSG00000126456.
DR Ensembl; ENST00000442265; ENSP00000400378; ENSG00000126456.
DR Ensembl; ENST00000596765; ENSP00000470512; ENSG00000126456.
DR Ensembl; ENST00000597198; ENSP00000469113; ENSG00000126456.
DR Ensembl; ENST00000599223; ENSP00000471358; ENSG00000126456.
DR Ensembl; ENST00000600022; ENSP00000472700; ENSG00000126456.
DR Ensembl; ENST00000601291; ENSP00000471896; ENSG00000126456.
DR GeneID; 3661; -.
DR KEGG; hsa:3661; -.
DR UCSC; uc002pou.3; human.
DR CTD; 3661; -.
DR GeneCards; GC19M050162; -.
DR HGNC; HGNC:6118; IRF3.
DR HPA; CAB013018; -.
DR HPA; HPA004895; -.
DR MIM; 603734; gene.
DR neXtProt; NX_Q14653; -.
DR PharmGKB; PA29917; -.
DR eggNOG; NOG42868; -.
DR HOGENOM; HOG000033705; -.
DR HOVERGEN; HBG105601; -.
DR KO; K05411; -.
DR OMA; CHTYWAV; -.
DR OrthoDB; EOG7CCBR1; -.
DR PhylomeDB; Q14653; -.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; IRF3; human.
DR EvolutionaryTrace; Q14653; -.
DR GeneWiki; IRF3; -.
DR GenomeRNAi; 3661; -.
DR NextBio; 14319; -.
DR PRO; PR:Q14653; -.
DR ArrayExpress; Q14653; -.
DR Bgee; Q14653; -.
DR CleanEx; HS_IRF3; -.
DR Genevestigator; Q14653; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0003677; F:DNA binding; NAS:BHF-UCL.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; IEA:InterPro.
DR GO; GO:0003712; F:transcription cofactor activity; TAS:ProtInc.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; TAS:UniProtKB.
DR GO; GO:0071359; P:cellular response to dsRNA; IEA:Ensembl.
DR GO; GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
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:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0050689; P:negative regulation of defense response to virus by host; IEA:Ensembl.
DR GO; GO:0045358; P:negative regulation of interferon-beta biosynthetic process; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome.
DR GO; GO:0050715; P:positive regulation of cytokine secretion; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; 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:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0006366; P:transcription from RNA polymerase II promoter; TAS:ProtInc.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045351; P:type I interferon biosynthetic process; IEA:Ensembl.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 2.60.200.10; -; 1.
DR InterPro; IPR019817; Interferon_reg_fac_CS.
DR InterPro; IPR001346; Interferon_reg_fact_DNA-bd_dom.
DR InterPro; IPR019471; Interferon_reg_factor-3.
DR InterPro; IPR017855; SMAD_dom-like.
DR InterPro; IPR008984; SMAD_FHA_domain.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00605; IRF; 1.
DR Pfam; PF10401; IRF-3; 1.
DR PRINTS; PR00267; INTFRNREGFCT.
DR SMART; SM00348; IRF; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR PROSITE; PS00601; IRF_1; 1.
DR PROSITE; PS51507; IRF_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Antiviral defense;
KW Complete proteome; Cytoplasm; Disulfide bond; DNA-binding;
KW Host-virus interaction; Immunity; Innate immunity; Isopeptide bond;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1 427 Interferon regulatory factor 3.
FT /FTId=PRO_0000154553.
FT DNA_BIND 5 111 IRF tryptophan pentad repeat.
FT REGION 200 360 Involved in HERC5 binding.
FT MOTIF 139 149 Nuclear export signal.
FT COMPBIAS 151 191 Pro-rich.
FT DISULFID 267 289
FT CROSSLNK 193 193 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT CROSSLNK 360 360 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT CROSSLNK 366 366 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ISG15).
FT VAR_SEQ 1 146 Missing (in isoform 3).
FT /FTId=VSP_046911.
FT VAR_SEQ 56 104 AWAEATGAYVPGRDKPDLPTWKRNFRSALNRKEGLRLAEDR
FT SKDPHDPH -> ELGTFPSQTPLRTPMVEAVLLIPRKTFWM
FT SYWVTWCWPHSQIRDPQAWL (in isoform 5).
FT /FTId=VSP_047690.
FT VAR_SEQ 105 427 Missing (in isoform 5).
FT /FTId=VSP_047691.
FT VAR_SEQ 201 327 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_043319.
FT VAR_SEQ 328 427 DLITFTEGSGRSPRYALWFCVGESWPQDQPWTKRLVMVKVV
FT PTCLRALVEMARVGGASSLENTVDLHISNSHPLSLTSDQYK
FT AYLQDLVEGMDFQGPGES -> GSWAPRSDYLHGRKRTLTT
FT LCPLVLCGGVMAPGPAVDQEARDGQGCAHVPQGLGRNGPGR
FT GCLLPGEYCGPAHFQQPPTLPHLRPVQGLPAGLGGGHGFPG
FT PWGELSPRSSWCASNPPVPHHLNQ (in isoform 4).
FT /FTId=VSP_046912.
FT VARIANT 96 96 R -> Q (in dbSNP:rs968457).
FT /FTId=VAR_011901.
FT VARIANT 107 107 Y -> F (in dbSNP:rs34745118).
FT /FTId=VAR_049643.
FT VARIANT 377 377 E -> K (in dbSNP:rs1049486).
FT /FTId=VAR_011902.
FT VARIANT 427 427 S -> T (in dbSNP:rs7251).
FT /FTId=VAR_011903.
FT MUTAGEN 77 78 KR->NG: Abolishes nuclear localization.
FT MUTAGEN 86 87 RK->LQ: No effect on subcellular
FT localization.
FT MUTAGEN 139 140 IL->MM: Abolishes nuclear export.
FT MUTAGEN 193 193 K->R: Highly diminished ISGylation; when
FT associated with R-360 and R-366.
FT MUTAGEN 360 360 K->R: Highly diminished ISGylation; when
FT associated with R-193 and R-366.
FT MUTAGEN 366 366 K->R: Highly diminished ISGylation; when
FT associated with R-193 and R-360.
FT MUTAGEN 385 386 SS->AA: Complete loss of viral infection
FT induced phosphorylation.
FT MUTAGEN 385 385 S->A,D,E: Complete loss of viral
FT infection induced phosphorylation.
FT MUTAGEN 386 386 S->A,D,E: Complete loss of viral
FT infection induced phosphorylation.
FT MUTAGEN 396 405 SNSHPLSLTS->ANAHPLALAA: Complete loss of
FT viral infection induced phosphorylation.
FT MUTAGEN 396 405 SNSHPLSLTS->DNDHPLDLDD: Acts as a
FT constitutively activated IRF3.
FT MUTAGEN 396 398 SNS->ANA: Complete loss of viral
FT infection induced phosphorylation.
FT MUTAGEN 402 405 SLTS->ALAA: Complete loss of viral
FT infection induced phosphorylation.
FT HELIX 8 18
FT STRAND 25 27
FT STRAND 28 31
FT STRAND 33 37
FT STRAND 41 45
FT HELIX 49 51
FT HELIX 53 60
FT STRAND 66 69
FT HELIX 73 85
FT STRAND 90 96
FT STRAND 100 102
FT STRAND 104 109
FT HELIX 191 195
FT STRAND 202 210
FT STRAND 213 221
FT STRAND 226 229
FT STRAND 239 244
FT HELIX 248 250
FT HELIX 255 267
FT STRAND 272 277
FT STRAND 280 285
FT STRAND 287 289
FT STRAND 291 296
FT STRAND 308 310
FT STRAND 313 315
FT STRAND 317 321
FT HELIX 322 333
FT STRAND 343 348
FT STRAND 354 356
FT HELIX 357 360
FT STRAND 363 369
FT HELIX 370 383
FT STRAND 389 391
FT STRAND 401 403
FT HELIX 405 416
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
//
MIM
603734
*RECORD*
*FIELD* NO
603734
*FIELD* TI
*603734 INTERFERON REGULATORY FACTOR 3; IRF3
*FIELD* TX
CLONING
The virus-induced expression of interferon (IFN; e.g., 147570) genes in
read moreinfected cells involves the interplay of several constitutively
expressed and virus-activated transcription factors. A family of IFN
regulatory factors (IRFs), which includes the activator IRF1 (147575)
and the repressor IRF2 (147576), have been shown to play a role in the
transcription of IFN genes as well as IFN-stimulated genes. By searching
an EST database for sequences that are similar to IRF1 and IRF2, Au et
al. (1995) identified IRF3, a novel member of the IRF family. The IRF3
gene is present in a single copy in the human genome. Northern blot
analysis detected a 1.6-kb constitutively expressed IRF3 transcript. The
deduced 427-amino acid IRF3 protein is 34 to 40% identical to other
members of the IRF family in the N-terminal region. Au et al. (1995)
showed that IRF3 is a 50-kD protein.
MAPPING
By linkage analysis using a highly polymorphic marker located in an
intron of IFR3, Bellingham et al. (1998) mapped the IRF3 gene to
19q13.3-q13.4, between D19S604 and D19S206.
GENE FUNCTION
Au et al. (1995) showed that IRF3 bound specifically to the
IFN-stimulated response element (ISRE), but not to the IRF1-binding site
positive regulatory domain (PRD)-I, a DNA-binding specificity similar to
that of ISGF3 (see 147574). Although IRF3 increased transcriptional
activity from an ISRE-containing promoter, expression of IRF3 as a Gal4
fusion protein did not activate expression of a chloramphenicol
acetyltransferase (CAT) reporter gene containing repeats of the
Gal4-binding sites. Au et al. (1995) suggested that IRF3 increases
transcriptional activity of targeted promoters through association with
another transcriptional activator(s).
Weaver et al. (1998) identified IRF3 as a component of DRAF1
(double-stranded RNA-activated factor-1), a positive regulator of
IFN-stimulated gene transcription that functions as a direct response to
viral infection. They demonstrated that IRF3 preexists in the cytoplasm
of uninfected cells and translocates to the nucleus following viral
infection. Translocation of IRF3 was accompanied by an increase in
serine and threonine phosphorylation. The transcriptional activators
CREBBP (600140) and EP300 (602700) coimmunoprecipitated with IRF3 only
subsequent to viral infection, and the authors stated that these are
also subunits of DRAF1.
Wathelet et al. (1998) identified a virus-activated factor (VAF) that
binds to a regulatory element shared by different virus-inducible genes.
VAF contains 2 members of the IRF family of transcriptional activator
proteins, IRF3 and IRF7 (605047), and the transcriptional coactivator
proteins p300 (602700) and CBP (600140). Remarkably, VAF and recombinant
IRF3 and IRF7 proteins bind weakly to the IFNB (see 147640) gene
promoter in vitro. However, in virus-infected cells, both proteins are
recruited to the endogenous IFNB promoter as part of a protein complex
that includes ATF2/c-jun (123811, 165160) and NF-kappa-B (see 164011).
These observations demonstrated the coordinate activation of multiple
transcriptional activator proteins and their highly cooperative assembly
into a transcriptional enhancer complex in vivo.
Sharma et al. (2003) demonstrated that IKKE (605048) and TANK-binding
kinase-1 (TBK1; 604834) are components of the virus-activated kinase
(VAK) that phosphorylate IRF3 and IRF7 (605047). They demonstrated an
essential role for an IKK-related kinase pathway in triggering the host
antiviral response to viral infection. Sharma et al. (2003) demonstrated
that expression of IKKE or TBK1 is sufficient to induce phosphorylation
of IRF3 and IRF7. This modification permits IRF3 dimerization and
translocation to the nucleus, where it induces transcription of
interferon and ISG56 genes.
Foy et al. (2003) showed that the hepatitis C virus NS3/4A serine
protease blocks the phosphorylation and effector action of IRF3 to
generate persistent infection. Disruption of the NS3/4A protease
function by mutation or a ketoamide peptidomimetic inhibitor relieved
this blockade and restored IRF3 phosphorylation after cellular challenge
with an unrelated virus. Foy et al. (2003) also showed that
dominant-negative or constitutively active IRF3 mutants, respectively,
enhanced or suppressed hepatitis C virus RNA replication in hepatoma
cells. Foy et al. (2003) concluded that the NS3/4A protease represents a
dual therapeutic target, the inhibition of which may both block viral
replication and restore IRF3 control of hepatitis C infection.
Using microarray technology to compare gene expression profiles of mouse
B lymphocytes stimulated with CD40LG (300386) or lipopolysaccharide,
Doyle et al. (2002) identified IRF3 as a factor specifically induced by
stimulation of TLR3 (603029) or TLR4 (603030), but not by TLR2 (603028),
TLR9 (605474), or CD40 (109535). The primary response genes induced by
this activation were coregulated by the NFKB pathway, common for both
TLRs and TNFRs, and the IRF3 pathway. Additional secondary response
genes were activated by autocrine and paracrine secretion of IFNB.
Selective TLR3/TLR4-IRF3 pathway activation potently inhibited viral
replication. Doyle et al. (2002) concluded that TLR3 and TLR4 have
evolutionarily diverged from other TLRs to activate IRF3, which mediates
a specific gene program responsible for innate antiviral responses.
Stetson and Medzhitov (2006) found that cytosolic DNA activated a potent
type I interferon response to the invasive bacterium Listeria
monocytogenes in mice. The noninvasive Legionella pneumophila triggered
an identical response through its type IV secretion system. Transfection
of 45-bp DNA oligonucleotides devoid of contiguous CpG into different
murine cell types recapitulated the interferon-inducing activity of
Listeria and Legionella in an Irf3-dependent, TLR-independent manner.
Microarray analysis revealed that cytosolic DNA activated a unique but
overlapping gene expression program compared with Tlr9- and Rigi (DDX58;
609631)/Mda5 (IFIH1; 606951)-dependent responses.
Manel et al. (2010) showed that, when dendritic cell resistance to
infection is circumvented, HIV-1 induces dendritic cell maturation, an
antiviral type I interferon response, and activation of T cells. This
innate response is dependent on the interaction of newly synthesized
HIV-1 capsid with cellular cyclophilin A (CYPA; 123840) and the
subsequent activation of the transcription factor IRF3. Because the
peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to
promote infectivity, the results of Manel et al. (2010) indicated that
capsid conformation has evolved under opposing selective pressures for
infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1
exists in dendritic cells and mediates an antiviral immune response, but
it is not typically engaged owing to the absence of dendritic cell
infection.
Cytosolic DNA induces interferons through the production of cyclic
guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or
cGAMP), which binds to and activates the adaptor protein STING (612374).
Through biochemical fractionation and quantitative mass spectrometry,
Sun et al. (2013) identified a cGAMP synthase (cGAS; 613973), which
belongs to the nucleotidyltransferase family. Overexpression of cGAS
activated the transcription factor IRF3 and induced interferon-beta
(147640) in a STING-dependent manner. Knockdown of cGAS inhibited IRF3
activation and interferon-beta induction by DNA transfection or DNA
virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP
synthesis. Sun et al. (2013) concluded that cGAS is a cytosolic DNA
sensor that induces interferons by producing the second messenger cGAMP.
Wu et al. (2013) found that mammalian cytosolic extracts synthesized
cGAMP in vitro from adenosine triphosphate (ATP) and guanosine
triphosphate (GTP) in the presence of DNA but not RNA. DNA transfection
or DNA virus infection of mammalian cells also triggered cGAMP
production. cGAMP bound to STING, leading to the activation of IRF3 and
induction of interferon-beta. Thus, Wu et al. (2013) concluded that
cGAMP is present in metazoans and functions as an endogenous second
messenger that triggers interferon production in response to cytosolic
DNA.
BIOCHEMICAL FEATURES
Escalante et al. (2007) cocrystalized the DNA-binding domain of human
IRF3 (amino acids 1 to 113) with a 33-bp sequence covering the PRDIII-I
region of the IFN-beta enhancer and resolved the structure to
2.3-angstrom resolution. They found that 4 IRF3 DNA-binding domains came
together in tandem on the PRDIII-I element to bind both consensus and
nonconsensus sequences. The ability of IRF3 DNA-binding domains to bind
these sites derived in part from 2 nonconserved arginines (arg78 and
arg86) that partook in alternate protein-DNA contacts. The protein-DNA
contacts were highly overlapped, and all 4 IRF3-binding sites were
required for gene activation in vivo.
MOLECULAR GENETICS
Bigham et al. (2011) tested 360 common haplotype-tagging and/or
functional SNPs in 86 genes encoding immune function regulators in 422
individuals with symptomatic West Nile virus (WNV; see 610379)
infections and 331 WNV-infected individuals without symptoms. After
correcting for multiple tests, they found that SNPs in IRF3 and MX1
(147150) were associated with symptomatic WNV infection and that a
single SNP in OAS1 (164350) was associated with increased risk of WNV
encephalitis and paralysis. Bigham et al. (2011) concluded that genetic
variation in the interferon response pathway is associated with risk for
symptomatic WNV infection and WNV disease progression.
*FIELD* RF
1. Au, W.-C.; Moore, P. A.; Lowther, W.; Juang, Y.-T.; Pitha, P. M.
: Identification of a member of the interferon regulatory factor family
that binds to the interferon-stimulated response element and activates
expression of interferon-induced genes. Proc. Nat. Acad. Sci. 92:
11657-11661, 1995.
2. Bellingham, J.; Gregory-Evans, K.; Gregory-Evans, C. Y.: Mapping
of human interferon regulatory factor 3 (IRF3) to chromosome 19q13.3-13.4
by an intragenic polymorphic marker. Ann. Hum. Genet. 62: 231-234,
1998.
3. Bigham, A. W.; Buckingham, K. J.; Husain, S.; Emond, M. J.; Bofferding,
K. M.; Gildersleeve, H.; Rutherford, A.; Astakhova, N. M.; Perelygin,
A. A.; Busch, M. P.; Murray, K. O.; Sejvar, J. J.; Green, S.; Kriesel,
J.; Brinton, M. A.; Bamshad, M.: Host genetic risk factors for West
Nile virus infection and disease progression. PLoS One 6: e24745,
2011. Note: Electronic Article.
4. Doyle, S. E.; Vaidya, S. A.; O'Connell, R.; Dadgostar, H.; Dempsey,
P. W.; Wu, T.-T.; Rao, G.; Sun, R.; Haberland, M. E.; Modlin, R. L.;
Cheng, G.: IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17:
251-263, 2002.
5. Escalante, C. R.; Nistal-Villan, E.; Shen, L.; Garcia-Sastre, A.;
Aggarwal, A. K.: Structure of IRF-3 bound to the PRDIII-I regulatory
element of the human interferon-beta enhancer. Molec. Cell 26: 703-716,
2007.
6. Foy, E.; Li, K.; Wang, C.; Sumpter, R., Jr.; Ikeda, M.; Lemon,
S. M.; Gale, M., Jr.: Regulation of interferon regulatory factor-3
by the hepatitis C virus serine protease. Science 300: 1145-1148,
2003.
7. Manel, N.; Hogstad, B.; Wang, Y.; Levy, D. E.; Unutmaz, D.; Littman,
D. R.: A cryptic sensor for HIV-1 activates antiviral innate immunity
in dendritic cells. Nature 467: 214-217, 2010. Note: Erratum: Nature
470: 424 only, 2011.
8. Sharma, S.; tenOever, B. R.; Grandvaux, N.; Zhou, G.-P.; Lin, R.;
Hiscott, J.: Triggering the interferon antiviral response through
an IKK-related pathway. Science 300: 1148-1151, 2003.
9. Stetson, D. B.; Medzhitov, R.: Recognition of cytosolic DNA activates
an IRF3-dependent innate immune response. Immunity 24: 93-103, 2006.
10. Sun, L.; Wu, J.; Du, F.; Chen, X.; Chen, Z. J.: Cyclic GMP-AMP
synthesis is a cytosolic DNA sensor that activates the type I interferon
pathway. Science 339: 786-791, 2013.
11. Wathelet, M. G.; Lin, C. H.; Parekh, B. S.; Ronco, L. V.; Howley,
P. M.; Maniatis, T.: Virus infection induces the assembly of coordinately
activated transcription factors on the IFN-beta enhancer in vivo. Molec.
Cell 1: 507-518, 1998. Note: Erratum: Molec. Cell 3: 813 only, 1999.
12. Weaver, B. K.; Kumar, K. P.; Reich, N. C.: Interferon regulatory
factor 3 and CREB-binding protein/p300 are subunits of double-stranded
RNA-activated transcription factor DRAF1. Molec. Cell. Biol. 18:
1359-1368, 1998.
13. Wu, J.; Sun, L.; Chen, X.; Du, F.; Shi, H.; Chen, C.; Chen, Z.
J.: Cyclic GMP-AMP is an endogenous second messenger in innate immune
signaling by cytosolic DNA. Science 339: 826-830, 2013.
*FIELD* CN
Ada Hamosh - updated: 3/8/2013
Paul J. Converse - updated: 7/3/2012
Ada Hamosh - updated: 10/6/2010
Paul J. Converse - updated: 11/7/2008
Patricia A. Hartz - updated: 7/5/2007
Paul J. Converse - updated: 1/6/2004
Ada Hamosh - updated: 6/10/2003
*FIELD* CD
Sheryl A. Jankowski: 4/15/1999
*FIELD* ED
carol: 04/12/2013
alopez: 3/11/2013
terry: 3/8/2013
mgross: 7/20/2012
terry: 7/3/2012
alopez: 7/6/2011
alopez: 10/7/2010
terry: 10/6/2010
mgross: 11/10/2008
terry: 11/7/2008
mgross: 7/10/2007
terry: 7/5/2007
wwang: 10/27/2005
mgross: 1/6/2004
alopez: 6/11/2003
terry: 6/10/2003
carol: 6/13/2000
alopez: 8/9/1999
psherman: 4/16/1999
*RECORD*
*FIELD* NO
603734
*FIELD* TI
*603734 INTERFERON REGULATORY FACTOR 3; IRF3
*FIELD* TX
CLONING
The virus-induced expression of interferon (IFN; e.g., 147570) genes in
read moreinfected cells involves the interplay of several constitutively
expressed and virus-activated transcription factors. A family of IFN
regulatory factors (IRFs), which includes the activator IRF1 (147575)
and the repressor IRF2 (147576), have been shown to play a role in the
transcription of IFN genes as well as IFN-stimulated genes. By searching
an EST database for sequences that are similar to IRF1 and IRF2, Au et
al. (1995) identified IRF3, a novel member of the IRF family. The IRF3
gene is present in a single copy in the human genome. Northern blot
analysis detected a 1.6-kb constitutively expressed IRF3 transcript. The
deduced 427-amino acid IRF3 protein is 34 to 40% identical to other
members of the IRF family in the N-terminal region. Au et al. (1995)
showed that IRF3 is a 50-kD protein.
MAPPING
By linkage analysis using a highly polymorphic marker located in an
intron of IFR3, Bellingham et al. (1998) mapped the IRF3 gene to
19q13.3-q13.4, between D19S604 and D19S206.
GENE FUNCTION
Au et al. (1995) showed that IRF3 bound specifically to the
IFN-stimulated response element (ISRE), but not to the IRF1-binding site
positive regulatory domain (PRD)-I, a DNA-binding specificity similar to
that of ISGF3 (see 147574). Although IRF3 increased transcriptional
activity from an ISRE-containing promoter, expression of IRF3 as a Gal4
fusion protein did not activate expression of a chloramphenicol
acetyltransferase (CAT) reporter gene containing repeats of the
Gal4-binding sites. Au et al. (1995) suggested that IRF3 increases
transcriptional activity of targeted promoters through association with
another transcriptional activator(s).
Weaver et al. (1998) identified IRF3 as a component of DRAF1
(double-stranded RNA-activated factor-1), a positive regulator of
IFN-stimulated gene transcription that functions as a direct response to
viral infection. They demonstrated that IRF3 preexists in the cytoplasm
of uninfected cells and translocates to the nucleus following viral
infection. Translocation of IRF3 was accompanied by an increase in
serine and threonine phosphorylation. The transcriptional activators
CREBBP (600140) and EP300 (602700) coimmunoprecipitated with IRF3 only
subsequent to viral infection, and the authors stated that these are
also subunits of DRAF1.
Wathelet et al. (1998) identified a virus-activated factor (VAF) that
binds to a regulatory element shared by different virus-inducible genes.
VAF contains 2 members of the IRF family of transcriptional activator
proteins, IRF3 and IRF7 (605047), and the transcriptional coactivator
proteins p300 (602700) and CBP (600140). Remarkably, VAF and recombinant
IRF3 and IRF7 proteins bind weakly to the IFNB (see 147640) gene
promoter in vitro. However, in virus-infected cells, both proteins are
recruited to the endogenous IFNB promoter as part of a protein complex
that includes ATF2/c-jun (123811, 165160) and NF-kappa-B (see 164011).
These observations demonstrated the coordinate activation of multiple
transcriptional activator proteins and their highly cooperative assembly
into a transcriptional enhancer complex in vivo.
Sharma et al. (2003) demonstrated that IKKE (605048) and TANK-binding
kinase-1 (TBK1; 604834) are components of the virus-activated kinase
(VAK) that phosphorylate IRF3 and IRF7 (605047). They demonstrated an
essential role for an IKK-related kinase pathway in triggering the host
antiviral response to viral infection. Sharma et al. (2003) demonstrated
that expression of IKKE or TBK1 is sufficient to induce phosphorylation
of IRF3 and IRF7. This modification permits IRF3 dimerization and
translocation to the nucleus, where it induces transcription of
interferon and ISG56 genes.
Foy et al. (2003) showed that the hepatitis C virus NS3/4A serine
protease blocks the phosphorylation and effector action of IRF3 to
generate persistent infection. Disruption of the NS3/4A protease
function by mutation or a ketoamide peptidomimetic inhibitor relieved
this blockade and restored IRF3 phosphorylation after cellular challenge
with an unrelated virus. Foy et al. (2003) also showed that
dominant-negative or constitutively active IRF3 mutants, respectively,
enhanced or suppressed hepatitis C virus RNA replication in hepatoma
cells. Foy et al. (2003) concluded that the NS3/4A protease represents a
dual therapeutic target, the inhibition of which may both block viral
replication and restore IRF3 control of hepatitis C infection.
Using microarray technology to compare gene expression profiles of mouse
B lymphocytes stimulated with CD40LG (300386) or lipopolysaccharide,
Doyle et al. (2002) identified IRF3 as a factor specifically induced by
stimulation of TLR3 (603029) or TLR4 (603030), but not by TLR2 (603028),
TLR9 (605474), or CD40 (109535). The primary response genes induced by
this activation were coregulated by the NFKB pathway, common for both
TLRs and TNFRs, and the IRF3 pathway. Additional secondary response
genes were activated by autocrine and paracrine secretion of IFNB.
Selective TLR3/TLR4-IRF3 pathway activation potently inhibited viral
replication. Doyle et al. (2002) concluded that TLR3 and TLR4 have
evolutionarily diverged from other TLRs to activate IRF3, which mediates
a specific gene program responsible for innate antiviral responses.
Stetson and Medzhitov (2006) found that cytosolic DNA activated a potent
type I interferon response to the invasive bacterium Listeria
monocytogenes in mice. The noninvasive Legionella pneumophila triggered
an identical response through its type IV secretion system. Transfection
of 45-bp DNA oligonucleotides devoid of contiguous CpG into different
murine cell types recapitulated the interferon-inducing activity of
Listeria and Legionella in an Irf3-dependent, TLR-independent manner.
Microarray analysis revealed that cytosolic DNA activated a unique but
overlapping gene expression program compared with Tlr9- and Rigi (DDX58;
609631)/Mda5 (IFIH1; 606951)-dependent responses.
Manel et al. (2010) showed that, when dendritic cell resistance to
infection is circumvented, HIV-1 induces dendritic cell maturation, an
antiviral type I interferon response, and activation of T cells. This
innate response is dependent on the interaction of newly synthesized
HIV-1 capsid with cellular cyclophilin A (CYPA; 123840) and the
subsequent activation of the transcription factor IRF3. Because the
peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to
promote infectivity, the results of Manel et al. (2010) indicated that
capsid conformation has evolved under opposing selective pressures for
infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1
exists in dendritic cells and mediates an antiviral immune response, but
it is not typically engaged owing to the absence of dendritic cell
infection.
Cytosolic DNA induces interferons through the production of cyclic
guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or
cGAMP), which binds to and activates the adaptor protein STING (612374).
Through biochemical fractionation and quantitative mass spectrometry,
Sun et al. (2013) identified a cGAMP synthase (cGAS; 613973), which
belongs to the nucleotidyltransferase family. Overexpression of cGAS
activated the transcription factor IRF3 and induced interferon-beta
(147640) in a STING-dependent manner. Knockdown of cGAS inhibited IRF3
activation and interferon-beta induction by DNA transfection or DNA
virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP
synthesis. Sun et al. (2013) concluded that cGAS is a cytosolic DNA
sensor that induces interferons by producing the second messenger cGAMP.
Wu et al. (2013) found that mammalian cytosolic extracts synthesized
cGAMP in vitro from adenosine triphosphate (ATP) and guanosine
triphosphate (GTP) in the presence of DNA but not RNA. DNA transfection
or DNA virus infection of mammalian cells also triggered cGAMP
production. cGAMP bound to STING, leading to the activation of IRF3 and
induction of interferon-beta. Thus, Wu et al. (2013) concluded that
cGAMP is present in metazoans and functions as an endogenous second
messenger that triggers interferon production in response to cytosolic
DNA.
BIOCHEMICAL FEATURES
Escalante et al. (2007) cocrystalized the DNA-binding domain of human
IRF3 (amino acids 1 to 113) with a 33-bp sequence covering the PRDIII-I
region of the IFN-beta enhancer and resolved the structure to
2.3-angstrom resolution. They found that 4 IRF3 DNA-binding domains came
together in tandem on the PRDIII-I element to bind both consensus and
nonconsensus sequences. The ability of IRF3 DNA-binding domains to bind
these sites derived in part from 2 nonconserved arginines (arg78 and
arg86) that partook in alternate protein-DNA contacts. The protein-DNA
contacts were highly overlapped, and all 4 IRF3-binding sites were
required for gene activation in vivo.
MOLECULAR GENETICS
Bigham et al. (2011) tested 360 common haplotype-tagging and/or
functional SNPs in 86 genes encoding immune function regulators in 422
individuals with symptomatic West Nile virus (WNV; see 610379)
infections and 331 WNV-infected individuals without symptoms. After
correcting for multiple tests, they found that SNPs in IRF3 and MX1
(147150) were associated with symptomatic WNV infection and that a
single SNP in OAS1 (164350) was associated with increased risk of WNV
encephalitis and paralysis. Bigham et al. (2011) concluded that genetic
variation in the interferon response pathway is associated with risk for
symptomatic WNV infection and WNV disease progression.
*FIELD* RF
1. Au, W.-C.; Moore, P. A.; Lowther, W.; Juang, Y.-T.; Pitha, P. M.
: Identification of a member of the interferon regulatory factor family
that binds to the interferon-stimulated response element and activates
expression of interferon-induced genes. Proc. Nat. Acad. Sci. 92:
11657-11661, 1995.
2. Bellingham, J.; Gregory-Evans, K.; Gregory-Evans, C. Y.: Mapping
of human interferon regulatory factor 3 (IRF3) to chromosome 19q13.3-13.4
by an intragenic polymorphic marker. Ann. Hum. Genet. 62: 231-234,
1998.
3. Bigham, A. W.; Buckingham, K. J.; Husain, S.; Emond, M. J.; Bofferding,
K. M.; Gildersleeve, H.; Rutherford, A.; Astakhova, N. M.; Perelygin,
A. A.; Busch, M. P.; Murray, K. O.; Sejvar, J. J.; Green, S.; Kriesel,
J.; Brinton, M. A.; Bamshad, M.: Host genetic risk factors for West
Nile virus infection and disease progression. PLoS One 6: e24745,
2011. Note: Electronic Article.
4. Doyle, S. E.; Vaidya, S. A.; O'Connell, R.; Dadgostar, H.; Dempsey,
P. W.; Wu, T.-T.; Rao, G.; Sun, R.; Haberland, M. E.; Modlin, R. L.;
Cheng, G.: IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17:
251-263, 2002.
5. Escalante, C. R.; Nistal-Villan, E.; Shen, L.; Garcia-Sastre, A.;
Aggarwal, A. K.: Structure of IRF-3 bound to the PRDIII-I regulatory
element of the human interferon-beta enhancer. Molec. Cell 26: 703-716,
2007.
6. Foy, E.; Li, K.; Wang, C.; Sumpter, R., Jr.; Ikeda, M.; Lemon,
S. M.; Gale, M., Jr.: Regulation of interferon regulatory factor-3
by the hepatitis C virus serine protease. Science 300: 1145-1148,
2003.
7. Manel, N.; Hogstad, B.; Wang, Y.; Levy, D. E.; Unutmaz, D.; Littman,
D. R.: A cryptic sensor for HIV-1 activates antiviral innate immunity
in dendritic cells. Nature 467: 214-217, 2010. Note: Erratum: Nature
470: 424 only, 2011.
8. Sharma, S.; tenOever, B. R.; Grandvaux, N.; Zhou, G.-P.; Lin, R.;
Hiscott, J.: Triggering the interferon antiviral response through
an IKK-related pathway. Science 300: 1148-1151, 2003.
9. Stetson, D. B.; Medzhitov, R.: Recognition of cytosolic DNA activates
an IRF3-dependent innate immune response. Immunity 24: 93-103, 2006.
10. Sun, L.; Wu, J.; Du, F.; Chen, X.; Chen, Z. J.: Cyclic GMP-AMP
synthesis is a cytosolic DNA sensor that activates the type I interferon
pathway. Science 339: 786-791, 2013.
11. Wathelet, M. G.; Lin, C. H.; Parekh, B. S.; Ronco, L. V.; Howley,
P. M.; Maniatis, T.: Virus infection induces the assembly of coordinately
activated transcription factors on the IFN-beta enhancer in vivo. Molec.
Cell 1: 507-518, 1998. Note: Erratum: Molec. Cell 3: 813 only, 1999.
12. Weaver, B. K.; Kumar, K. P.; Reich, N. C.: Interferon regulatory
factor 3 and CREB-binding protein/p300 are subunits of double-stranded
RNA-activated transcription factor DRAF1. Molec. Cell. Biol. 18:
1359-1368, 1998.
13. Wu, J.; Sun, L.; Chen, X.; Du, F.; Shi, H.; Chen, C.; Chen, Z.
J.: Cyclic GMP-AMP is an endogenous second messenger in innate immune
signaling by cytosolic DNA. Science 339: 826-830, 2013.
*FIELD* CN
Ada Hamosh - updated: 3/8/2013
Paul J. Converse - updated: 7/3/2012
Ada Hamosh - updated: 10/6/2010
Paul J. Converse - updated: 11/7/2008
Patricia A. Hartz - updated: 7/5/2007
Paul J. Converse - updated: 1/6/2004
Ada Hamosh - updated: 6/10/2003
*FIELD* CD
Sheryl A. Jankowski: 4/15/1999
*FIELD* ED
carol: 04/12/2013
alopez: 3/11/2013
terry: 3/8/2013
mgross: 7/20/2012
terry: 7/3/2012
alopez: 7/6/2011
alopez: 10/7/2010
terry: 10/6/2010
mgross: 11/10/2008
terry: 11/7/2008
mgross: 7/10/2007
terry: 7/5/2007
wwang: 10/27/2005
mgross: 1/6/2004
alopez: 6/11/2003
terry: 6/10/2003
carol: 6/13/2000
alopez: 8/9/1999
psherman: 4/16/1999