FOXP3_HUMAN
ID FOXP3_HUMAN Reviewed; 431 AA.
AC Q9BZS1; A5HJT1; B7ZLG0; B9UN80; O60827; Q14DD8; Q4ZH51;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 210.
DE RecName: Full=Forkhead box protein P3;
DE AltName: Full=Scurfin;
DE Contains:
DE RecName: Full=Forkhead box protein P3, C-terminally processed;
DE Contains:
DE RecName: Full=Forkhead box protein P3 41 kDa form;
GN Name=FOXP3; Synonyms=IPEX; ORFNames=JM2;
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).
RX PubMed=11138001; DOI=10.1038/83784;
RA Brunkow M.E., Jeffery E.W., Hjerrild K.A., Paeper B., Clark L.B.,
RA Yasayko S.-A., Wilkinson J.E., Galas D., Ziegler S.F., Ramsdell F.;
RT "Disruption of a new forkhead/winged-helix protein, scurfin, results in the
RT fatal lymphoproliferative disorder of the scurfy mouse.";
RL Nat. Genet. 27:68-73(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Wang J., Liu Q., Zhang Y., Xu Z., Huang C.;
RT "Cloning and expression of the cDNA for FOXP3.";
RL Submitted (APR-2007) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Kaur G., Goodall J.C., Jarvis L.B., Gaston J.S.H.;
RT "Functional characterization of FOXP3 splice variants in human regulatory T
RT cells.";
RL Submitted (JUN-2008) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Lin L., Nong W., Li H., Ke R., Shen C., Zhong G., Zheng Z., Liang M.,
RA Huang B., Zhou G., Yang S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
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 [LARGE SCALE MRNA] OF 16-431 (ISOFORM 3).
RA Strom T.M., Nyakatura G., Hellebrand H., Drescher B., Rosenthal A.,
RA Meindl A.;
RT "Transcription map in Xp11.23.";
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP FUNCTION, AND INTERACTION WITH RELA AND NFATC2.
RX PubMed=15790681; DOI=10.1073/pnas.0501675102;
RA Bettelli E., Dastrange M., Oukka M.;
RT "Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to
RT repress cytokine gene expression and effector functions of T helper
RT cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:5138-5143(2005).
RN [9]
RP FUNCTION, AND INTERACTION WITH RUNX1.
RX PubMed=17377532; DOI=10.1038/nature05673;
RA Ono M., Yaguchi H., Ohkura N., Kitabayashi I., Nagamura Y., Nomura T.,
RA Miyachi Y., Tsukada T., Sakaguchi S.;
RT "Foxp3 controls regulatory T-cell function by interacting with
RT AML1/Runx1.";
RL Nature 446:685-689(2007).
RN [10]
RP FUNCTION, ACETYLATION, INTERACTION WITH KAT5; HDAC7 AND HDAC9, AND
RP SUBCELLULAR LOCATION.
RX PubMed=17360565; DOI=10.1073/pnas.0700298104;
RA Li B., Samanta A., Song X., Iacono K.T., Bembas K., Tao R., Basu S.,
RA Riley J.L., Hancock W.W., Shen Y., Saouaf S.J., Greene M.I.;
RT "FOXP3 interactions with histone acetyltransferase and class II histone
RT deacetylases are required for repression.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:4571-4576(2007).
RN [11]
RP FUNCTION, INTERACTION WITH RORA, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 95-LEU-LEU-96.
RX PubMed=18354202; DOI=10.4049/jimmunol.180.7.4785;
RA Du J., Huang C., Zhou B., Ziegler S.F.;
RT "Isoform-specific inhibition of ROR alpha-mediated transcriptional
RT activation by human FOXP3.";
RL J. Immunol. 180:4785-4792(2008).
RN [12]
RP FUNCTION, AND INTERACTION WITH RORC.
RX PubMed=18368049; DOI=10.1038/nature06878;
RA Zhou L., Lopes J.E., Chong M.M., Ivanov I.I., Min R., Victora G.D.,
RA Shen Y., Du J., Rubtsov Y.P., Rudensky A.Y., Ziegler S.F., Littman D.R.;
RT "TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by
RT antagonizing RORgammat function.";
RL Nature 453:236-240(2008).
RN [13]
RP PROTEOLYTIC PROCESSING.
RX PubMed=19117830; DOI=10.1074/jbc.m807322200;
RA de Zoeten E.F., Lee I., Wang L., Chen C., Ge G., Wells A.D., Hancock W.W.,
RA Ozkaynak E.;
RT "Foxp3 processing by proprotein convertases and control of regulatory T
RT cell function.";
RL J. Biol. Chem. 284:5709-5716(2009).
RN [14]
RP INTERACTION WITH IKZF3.
RX PubMed=20676092; DOI=10.1038/ni.1915;
RA Gandhi R., Kumar D., Burns E.J., Nadeau M., Dake B., Laroni A., Kozoriz D.,
RA Weiner H.L., Quintana F.J.;
RT "Activation of the aryl hydrocarbon receptor induces human type 1
RT regulatory T cell-like and Foxp3(+) regulatory T cells.";
RL Nat. Immunol. 11:846-853(2010).
RN [15]
RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, NUCLEAR EXPORT SIGNAL,
RP AND MUTAGENESIS OF LEU-69; LEU-71; LEU-74; LEU-76; 415-LYS-LYS-416;
RP LEU-242; LEU-246 AND LEU-248.
RX PubMed=22678915; DOI=10.1002/eji.201141838;
RA Magg T., Mannert J., Ellwart J.W., Schmid I., Albert M.H.;
RT "Subcellular localization of FOXP3 in human regulatory and nonregulatory T
RT cells.";
RL Eur. J. Immunol. 42:1627-1638(2012).
RN [16]
RP ACETYLATION AT LYS-31; LYS-263 AND LYS-268, AND DEACETYLATION BY SIRT1.
RX PubMed=22312127; DOI=10.4049/jimmunol.1100903;
RA Kwon H.S., Lim H.W., Wu J., Schnolzer M., Verdin E., Ott M.;
RT "Three novel acetylation sites in the Foxp3 transcription factor regulate
RT the suppressive activity of regulatory T cells.";
RL J. Immunol. 188:2712-2721(2012).
RN [17]
RP FUNCTION.
RX PubMed=23169781; DOI=10.1182/blood-2012-05-431023;
RA McMurchy A.N., Gillies J., Gizzi M.C., Riba M., Garcia-Manteiga J.M.,
RA Cittaro D., Lazarevic D., Di Nunzio S., Piras I.S., Bulfone A.,
RA Roncarolo M.G., Stupka E., Bacchetta R., Levings M.K.;
RT "A novel function for FOXP3 in humans: intrinsic regulation of conventional
RT T cells.";
RL Blood 121:1265-1275(2013).
RN [18]
RP REVIEW.
RX PubMed=24350059; DOI=10.3389/fonc.2013.00294;
RA Lozano T., Casares N., Lasarte J.J.;
RT "Searching for the Achilles Heel of FOXP3.";
RL Front. Oncol. 3:294-294(2013).
RN [19]
RP UBIQUITINATION, DEUBIQUITINATION, SUBCELLULAR LOCATION, AND INTERACTION
RP WITH USP7.
RX PubMed=23973222; DOI=10.1016/j.immuni.2013.05.018;
RA van Loosdregt J., Fleskens V., Fu J., Brenkman A.B., Bekker C.P.,
RA Pals C.E., Meerding J., Berkers C.R., Barbi J., Grone A., Sijts A.J.,
RA Maurice M.M., Kalkhoven E., Prakken B.J., Ovaa H., Pan F., Zaiss D.M.,
RA Coffer P.J.;
RT "Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7
RT increases Treg-cell-suppressive capacity.";
RL Immunity 39:259-271(2013).
RN [20]
RP INTERACTION WITH STUB1; HSPA8 AND HSPA1A/B, SUBCELLULAR LOCATION,
RP UBIQUITINATION, AND INDUCTION.
RX PubMed=23973223; DOI=10.1016/j.immuni.2013.08.006;
RA Chen Z., Barbi J., Bu S., Yang H.Y., Li Z., Gao Y., Jinasena D., Fu J.,
RA Lin F., Chen C., Zhang J., Yu N., Li X., Shan Z., Nie J., Gao Z., Tian H.,
RA Li Y., Yao Z., Zheng Y., Park B.V., Pan Z., Zhang J., Dang E., Li Z.,
RA Wang H., Luo W., Li L., Semenza G.L., Zheng S.G., Loser K., Tsun A.,
RA Greene M.I., Pardoll D.M., Pan F., Li B.;
RT "The ubiquitin ligase Stub1 negatively modulates regulatory T cell
RT suppressive activity by promoting degradation of the transcription factor
RT Foxp3.";
RL Immunity 39:272-285(2013).
RN [21]
RP INTERACTION WITH ZFP90.
RX PubMed=23543754; DOI=10.4049/jimmunol.1203561;
RA Huang C., Martin S., Pfleger C., Du J., Buckner J.H., Bluestone J.A.,
RA Riley J.L., Ziegler S.F.;
RT "Cutting Edge: a novel, human-specific interacting protein couples FOXP3 to
RT a chromatin-remodeling complex that contains KAP1/TRIM28.";
RL J. Immunol. 190:4470-4473(2013).
RN [22]
RP PHOSPHORYLATION AT SER-418, SUBCELLULAR LOCATION, INTERACTION WITH PPP1CA;
RP PPP1CB AND PPP1CG, MUTAGENESIS OF SER-418 AND SER-422, AND
RP DEPHOSPHORYLATION.
RX PubMed=23396208; DOI=10.1038/nm.3085;
RA Nie H., Zheng Y., Li R., Guo T.B., He D., Fang L., Liu X., Xiao L.,
RA Chen X., Wan B., Chin Y.E., Zhang J.Z.;
RT "Phosphorylation of FOXP3 controls regulatory T cell function and is
RT inhibited by TNF-alpha in rheumatoid arthritis.";
RL Nat. Med. 19:322-328(2013).
RN [23]
RP FUNCTION, AND ACETYLATION.
RX PubMed=24835996; DOI=10.1016/j.celrep.2014.04.021;
RA Xiao Y., Nagai Y., Deng G., Ohtani T., Zhu Z., Zhou Z., Zhang H., Ji M.Q.,
RA Lough J.W., Samanta A., Hancock W.W., Greene M.I.;
RT "Dynamic interactions between TIP60 and p300 regulate FOXP3 function
RT through a structural switch defined by a single lysine on TIP60.";
RL Cell Rep. 7:1471-1480(2014).
RN [24]
RP REVIEW ON FUNCTION.
RX PubMed=23947341; DOI=10.3109/08830185.2013.811657;
RA Vent-Schmidt J., Han J.M., MacDonald K.G., Levings M.K.;
RT "The role of FOXP3 in regulating immune responses.";
RL Int. Rev. Immunol. 33:110-128(2014).
RN [25]
RP REVIEW ON FUNCTION.
RX PubMed=24354325; DOI=10.3109/08830185.2013.863303;
RA Passerini L., Santoni de Sio F.R., Roncarolo M.G., Bacchetta R.;
RT "Forkhead box P3: the peacekeeper of the immune system.";
RL Int. Rev. Immunol. 33:129-145(2014).
RN [26]
RP REVIEW.
RX PubMed=24722479; DOI=10.1038/nri3650;
RA Ramsdell F., Ziegler S.F.;
RT "FOXP3 and scurfy: how it all began.";
RL Nat. Rev. Immunol. 14:343-349(2014).
RN [27]
RP REVIEW ON PTM.
RX PubMed=25047417; DOI=10.1016/j.it.2014.06.005;
RA van Loosdregt J., Coffer P.J.;
RT "Post-translational modification networks regulating FOXP3 function.";
RL Trends Immunol. 35:368-378(2014).
RN [28]
RP FUNCTION, AND INDUCTION.
RX PubMed=30513302; DOI=10.1016/j.devcel.2018.11.010;
RA Becher J., Simula L., Volpe E., Procaccini C., La Rocca C., D'Acunzo P.,
RA Cianfanelli V., Strappazzon F., Caruana I., Nazio F., Weber G.,
RA Gigantino V., Botti G., Ciccosanti F., Borsellino G., Campello S.,
RA Mandolesi G., De Bardi M., Fimia G.M., D'Amelio M., Ruffini F., Furlan R.,
RA Centonze D., Martino G., Braghetta P., Chrisam M., Bonaldo P., Matarese G.,
RA Locatelli F., Battistini L., Cecconi F.;
RT "AMBRA1 controls regulatory T-cell differentiation and homeostasis upstream
RT of the FOXO3-FOXP3 axis.";
RL Dev. Cell 47:592-607(2018).
RN [29] {ECO:0007744|PDB:3QRF}
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 336-417 IN COMPLEX WITH DNA AND
RP NFATC2, FUNCTION, SUBUNIT, DOMAIN FORK-HEAD, INTERACTION WITH NFATC2,
RP CHARACTERIZATION OF VARIANTS IPEX GLU-251 DEL; HIS-347; CYS-371 AND
RP ALA-373, AND MUTAGENESIS OF TRP-348; MET-370 AND ALA-372.
RX PubMed=21458306; DOI=10.1016/j.immuni.2011.02.017;
RA Bandukwala H.S., Wu Y., Feuerer M., Chen Y., Barboza B., Ghosh S.,
RA Stroud J.C., Benoist C., Mathis D., Rao A., Chen L.;
RT "Structure of a domain-swapped FOXP3 dimer on DNA and its function in
RT regulatory T cells.";
RL Immunity 34:479-491(2011).
RN [30] {ECO:0007744|PDB:4WK8}
RP X-RAY CRYSTALLOGRAPHY (3.40 ANGSTROMS) OF 336-417 IN COMPLEX WITH DNA,
RP FUNCTION, AND SUBUNIT.
RX PubMed=25567984; DOI=10.1093/nar/gku1373;
RA Chen Y., Chen C., Zhang Z., Liu C.C., Johnson M.E., Espinoza C.A.,
RA Edsall L.E., Ren B., Zhou X.J., Grant S.F., Wells A.D., Chen L.;
RT "DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-
RT range chromosomal interactions.";
RL Nucleic Acids Res. 43:1268-1282(2015).
RN [31]
RP VARIANT IPEX GLU-251 DEL.
RX PubMed=11120765; DOI=10.1172/jci11679;
RA Chatila T.A., Blaeser F., Ho N., Lederman H.M., Voulgaropoulos C.,
RA Helms C., Bowcock A.M.;
RT "JM2, encoding a fork head-related protein, is mutated in X-linked
RT autoimmunity-allergic disregulation syndrome.";
RL J. Clin. Invest. 106:R75-R81(2000).
RN [32]
RP VARIANT IPEX VAL-363.
RX PubMed=11768393; DOI=10.1136/jmg.38.12.874;
RA Kobayashi I., Shiari R., Yamada M., Kawamura N., Okano M., Yara A.,
RA Iguchi A., Ishikawa N., Ariga T., Sakiyama Y., Ochs H.D., Kobayashi K.;
RT "Novel mutations of FOXP3 in two Japanese patients with immune
RT dysregulation, polyendocrinopathy, enteropathy, X linked syndrome (IPEX).";
RL J. Med. Genet. 38:874-876(2001).
RN [33]
RP VARIANTS IPEX CYS-371; THR-384 AND TRP-397.
RX PubMed=11137992; DOI=10.1038/83707;
RA Wildin R.S., Ramsdell F., Peake J., Faravelli F., Casanova J.-L., Buist N.,
RA Levy-Lahad E., Mazzella M., Goulet O., Perroni L., Bricarelli F.D.,
RA Byrne G., McEuen M., Proll S., Appleby M., Brunkow M.E.;
RT "X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy
RT syndrome is the human equivalent of mouse scurfy.";
RL Nat. Genet. 27:18-20(2001).
RN [34]
RP VARIANT IPEX THR-384.
RX PubMed=11137993; DOI=10.1038/83713;
RA Bennett C.L., Christie J., Ramsdell F., Brunkow M.E., Ferguson P.J.,
RA Whitesell L., Kelly T.E., Saulsbury F.T., Chance P.F., Ochs H.D.;
RT "The immune dysregulation, polyendocrinopathy, enteropathy, X-linked
RT syndrome (IPEX) is caused by mutations of FOXP3.";
RL Nat. Genet. 27:20-21(2001).
RN [35]
RP VARIANTS IPEX PRO-242; LEU-324; ALA-339; HIS-347; ALA-373; CYS-374 AND
RP THR-384, AND CHARACTERIZATION OF VARIANTS IPEX PRO-242; LEU-324; ALA-339;
RP HIS-347; ALA-373; CYS-374 AND THR-384.
RX PubMed=18951619; DOI=10.1016/j.jaci.2008.09.027;
RA Gambineri E., Perroni L., Passerini L., Bianchi L., Doglioni C., Meschi F.,
RA Bonfanti R., Sznajer Y., Tommasini A., Lawitschka A., Junker A.,
RA Dunstheimer D., Heidemann P.H., Cazzola G., Cipolli M., Friedrich W.,
RA Janic D., Azzi N., Richmond E., Vignola S., Barabino A., Chiumello G.,
RA Azzari C., Roncarolo M.G., Bacchetta R.;
RT "Clinical and molecular profile of a new series of patients with immune
RT dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome:
RT inconsistent correlation between forkhead box protein 3 expression and
RT disease severity.";
RL J. Allergy Clin. Immunol. 122:1105-1112(2008).
CC -!- FUNCTION: Transcriptional regulator which is crucial for the
CC development and inhibitory function of regulatory T-cells (Treg)
CC (PubMed:17377532, PubMed:21458306, PubMed:30513302, PubMed:23947341,
CC PubMed:24354325, PubMed:24722479, PubMed:24835996). Plays an essential
CC role in maintaining homeostasis of the immune system by allowing the
CC acquisition of full suppressive function and stability of the Treg
CC lineage, and by directly modulating the expansion and function of
CC conventional T-cells (PubMed:23169781). Can act either as a
CC transcriptional repressor or a transcriptional activator depending on
CC its interactions with other transcription factors, histone acetylases
CC and deacetylases (PubMed:17377532, PubMed:21458306, PubMed:23947341,
CC PubMed:24354325, PubMed:24722479). The suppressive activity of Treg
CC involves the coordinate activation of many genes, including CTLA4 and
CC TNFRSF18 by FOXP3 along with repression of genes encoding cytokines
CC such as interleukin-2 (IL2) and interferon-gamma (IFNG)
CC (PubMed:17377532, PubMed:21458306, PubMed:23947341, PubMed:24354325,
CC PubMed:24722479). Inhibits cytokine production and T-cell effector
CC function by repressing the activity of two key transcription factors,
CC RELA and NFATC2 (PubMed:15790681). Mediates transcriptional repression
CC of IL2 via its association with histone acetylase KAT5 and histone
CC deacetylase HDAC7 (PubMed:17360565). Can activate the expression of
CC TNFRSF18, IL2RA and CTLA4 and repress the expression of IL2 and IFNG
CC via its association with transcription factor RUNX1 (PubMed:17377532).
CC Inhibits the differentiation of IL17 producing helper T-cells (Th17) by
CC antagonizing RORC function, leading to down-regulation of IL17
CC expression, favoring Treg development (PubMed:18368049). Inhibits the
CC transcriptional activator activity of RORA (PubMed:18354202). Can
CC repress the expression of IL2 and IFNG via its association with
CC transcription factor IKZF4 (By similarity).
CC {ECO:0000250|UniProtKB:Q99JB6, ECO:0000269|PubMed:15790681,
CC ECO:0000269|PubMed:17360565, ECO:0000269|PubMed:17377532,
CC ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:18368049,
CC ECO:0000269|PubMed:21458306, ECO:0000269|PubMed:23169781,
CC ECO:0000269|PubMed:24835996, ECO:0000269|PubMed:30513302,
CC ECO:0000303|PubMed:23947341, ECO:0000303|PubMed:24354325,
CC ECO:0000303|PubMed:24722479}.
CC -!- SUBUNIT: Homodimer (PubMed:21458306, PubMed:25567984). Dimerization is
CC essential for its transcriptional regulator activity (PubMed:21458306).
CC Interacts with IKZF3. Isoform 1 (via LXXLL motif), but not isoform 2,
CC interacts with isoform 4 of RORA (via AF-2 motif). Interacts with
CC STUB1, HSPA8 and HSPA1A/B. Interacts with PPP1CA, PPP1CB and PPP1CG.
CC Interacts with KAT5 and HDAC7. Interacts with HDAC9 in the absence of
CC T-cell stimulation. Interacts with USP7. Interacts with isoform 2 of
CC ZFP90 and can form a complex with TRIM28 in the presence of isoform 2
CC of ZFP90. Interacts with RUNX1. Interacts with RORC. Interacts with
CC RELA and NFATC2. Interacts with RUNX2, RUNX3 and IKZF4 (By similarity).
CC {ECO:0000250|UniProtKB:Q99JB6, ECO:0000269|PubMed:15790681,
CC ECO:0000269|PubMed:17360565, ECO:0000269|PubMed:17377532,
CC ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:18368049,
CC ECO:0000269|PubMed:20676092, ECO:0000269|PubMed:21458306,
CC ECO:0000269|PubMed:23396208, ECO:0000269|PubMed:23543754,
CC ECO:0000269|PubMed:23973222, ECO:0000269|PubMed:23973223,
CC ECO:0000269|PubMed:25567984}.
CC -!- INTERACTION:
CC Q9BZS1; P53539: FOSB; NbExp=3; IntAct=EBI-983719, EBI-2806743;
CC Q9BZS1; Q9UKT9: IKZF3; NbExp=2; IntAct=EBI-983719, EBI-747204;
CC Q9BZS1; Q9BYR6: KRTAP3-3; NbExp=3; IntAct=EBI-983719, EBI-3957694;
CC Q9BZS1; Q3LI66: KRTAP6-2; NbExp=3; IntAct=EBI-983719, EBI-11962084;
CC Q9BZS1; Q8IUC2: KRTAP8-1; NbExp=3; IntAct=EBI-983719, EBI-10261141;
CC Q9BZS1; P62136: PPP1CA; NbExp=2; IntAct=EBI-983719, EBI-357253;
CC Q9BZS1; P86479: PRR20C; NbExp=4; IntAct=EBI-983719, EBI-10172814;
CC Q9BZS1; P86480: PRR20D; NbExp=4; IntAct=EBI-983719, EBI-12754095;
CC Q9BZS1; P86478: PRR20E; NbExp=5; IntAct=EBI-983719, EBI-12700196;
CC Q9BZS1; Q93062: RBPMS; NbExp=6; IntAct=EBI-983719, EBI-740322;
CC Q9BZS1; Q93062-3: RBPMS; NbExp=3; IntAct=EBI-983719, EBI-740343;
CC Q9BZS1; P35398-4: RORA; NbExp=5; IntAct=EBI-983719, EBI-11295807;
CC Q9BZS1; Q9UNE7: STUB1; NbExp=7; IntAct=EBI-983719, EBI-357085;
CC Q9BZS1; Q9H0E7: USP44; NbExp=3; IntAct=EBI-983719, EBI-2512823;
CC Q9BZS1; Q8TF47-3: ZFP90; NbExp=4; IntAct=EBI-983719, EBI-11419904;
CC Q9BZS1; PRO_0000449621 [P0DTD1]: rep; Xeno; NbExp=4; IntAct=EBI-983719, EBI-25492388;
CC Q9BZS1-1; Q8WUI4: HDAC7; NbExp=2; IntAct=EBI-9695448, EBI-1048378;
CC Q9BZS1-1; Q92993: KAT5; NbExp=2; IntAct=EBI-9695448, EBI-399080;
CC Q9BZS1-1; P11309-1: PIM1; NbExp=3; IntAct=EBI-9695448, EBI-1018629;
CC Q9BZS1-2; Q8WUI4: HDAC7; NbExp=2; IntAct=EBI-16338471, EBI-1048378;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00089,
CC ECO:0000269|PubMed:17360565, ECO:0000269|PubMed:18354202,
CC ECO:0000269|PubMed:22678915, ECO:0000269|PubMed:23396208,
CC ECO:0000269|PubMed:23973222, ECO:0000269|PubMed:23973223}. Cytoplasm
CC {ECO:0000269|PubMed:22678915}. Note=Predominantly expressed in the
CC cytoplasm in activated conventional T-cells whereas predominantly
CC expressed in the nucleus in regulatory T-cells (Treg). The 41 kDa form
CC derived by proteolytic processing is found exclusively in the chromatin
CC fraction of activated Treg cells (By similarity).
CC {ECO:0000250|UniProtKB:Q99JB6, ECO:0000269|PubMed:22678915}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q9BZS1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BZS1-2; Sequence=VSP_015796;
CC Name=3;
CC IsoId=Q9BZS1-3; Sequence=VSP_015796, VSP_036418;
CC Name=4;
CC IsoId=Q9BZS1-4; Sequence=VSP_047859;
CC -!- INDUCTION: Down-regulated in regulatory T-cells (Treg) during
CC inflammation (PubMed:23973223). Up-regulated by FOXO3
CC (PubMed:30513302). {ECO:0000269|PubMed:23973223,
CC ECO:0000269|PubMed:30513302}.
CC -!- DOMAIN: The fork-head DNA-binding domain is essential for its
CC dimerization and interaction with NFATC2.
CC {ECO:0000269|PubMed:21458306}.
CC -!- PTM: Polyubiquitinated, leading to its proteasomal degradation in
CC regulatory T-cells (Treg) which is mediated by STUB1 in a HSPA1A/B-
CC dependent manner. Deubiquitinated by USP7 leading to increase in
CC protein stability. {ECO:0000269|PubMed:23973222,
CC ECO:0000269|PubMed:23973223}.
CC -!- PTM: Phosphorylation at Ser-418 regulates its transcriptional repressor
CC activity and consequently, regulatory T-cells (Treg) suppressive
CC function. Dephosphorylated at Ser-418 by protein phosphatase 1 (PP1) in
CC Treg cells derived from patients with rheumatoid arthritis.
CC Phosphorylation by CDK2 negatively regulates its transcriptional
CC activity and protein stability (By similarity).
CC {ECO:0000250|UniProtKB:Q99JB6, ECO:0000269|PubMed:23396208}.
CC -!- PTM: Acetylation on lysine residues stabilizes FOXP3 and promotes
CC differentiation of T-cells into induced regulatory T-cells (iTregs)
CC associated with suppressive functions (PubMed:17360565,
CC PubMed:24835996). Acetylation is mediated by a coordinated action of
CC KAT5 and EP300/p300 acetyltransferases: EP300/p300 is required to
CC enhance KAT5 autoacetylation, promoting acetylation of FOXP3 by KAT5
CC (PubMed:24835996). Deacetylated by SIRT1 (PubMed:22312127).
CC {ECO:0000269|PubMed:17360565, ECO:0000269|PubMed:22312127,
CC ECO:0000269|PubMed:24835996}.
CC -!- PTM: Undergoes proteolytic cleavage in activated regulatory T-cells
CC (Treg), and can be cleaved at either the N- or C-terminal site, or at
CC both sites. {ECO:0000269|PubMed:19117830}.
CC -!- DISEASE: Immunodeficiency polyendocrinopathy, enteropathy, X-linked
CC syndrome (IPEX) [MIM:304790]: Characterized by neonatal onset insulin-
CC dependent diabetes mellitus, infections, secretory diarrhea,
CC thrombocytopenia, anemia and eczema. It is usually lethal in infancy.
CC {ECO:0000269|PubMed:11120765, ECO:0000269|PubMed:11137992,
CC ECO:0000269|PubMed:11137993, ECO:0000269|PubMed:11768393,
CC ECO:0000269|PubMed:18951619, ECO:0000269|PubMed:21458306}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FOXP3ID44129chXp11.html";
CC -!- WEB RESOURCE: Name=FOXP3base; Note=FOXP3 mutation db;
CC URL="http://structure.bmc.lu.se/idbase/FOXP3base/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=FOXP3 entry;
CC URL="https://en.wikipedia.org/wiki/FOXP3";
CC ---------------------------------------------------------------------------
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DR EMBL; AF277993; AAG53607.1; -; mRNA.
DR EMBL; EF534714; ABQ15210.1; -; mRNA.
DR EMBL; EU855812; ACJ46653.1; -; mRNA.
DR EMBL; DQ010327; AAY27088.1; -; mRNA.
DR EMBL; AF235097; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC113401; AAI13402.1; -; mRNA.
DR EMBL; BC113403; AAI13404.1; -; mRNA.
DR EMBL; BC143785; AAI43786.1; -; mRNA.
DR EMBL; AJ005891; CAA06748.1; -; mRNA.
DR CCDS; CCDS14323.1; -. [Q9BZS1-1]
DR CCDS; CCDS48109.1; -. [Q9BZS1-2]
DR RefSeq; NP_001107849.1; NM_001114377.1. [Q9BZS1-2]
DR RefSeq; NP_054728.2; NM_014009.3. [Q9BZS1-1]
DR PDB; 3QRF; X-ray; 2.80 A; F/G/H/I=336-417.
DR PDB; 4WK8; X-ray; 3.40 A; F/G=336-417.
DR PDBsum; 3QRF; -.
DR PDBsum; 4WK8; -.
DR AlphaFoldDB; Q9BZS1; -.
DR SMR; Q9BZS1; -.
DR BioGRID; 119170; 85.
DR CORUM; Q9BZS1; -.
DR DIP; DIP-36584N; -.
DR IntAct; Q9BZS1; 74.
DR MINT; Q9BZS1; -.
DR STRING; 9606.ENSP00000365380; -.
DR iPTMnet; Q9BZS1; -.
DR PhosphoSitePlus; Q9BZS1; -.
DR SwissPalm; Q9BZS1; -.
DR BioMuta; FOXP3; -.
DR DMDM; 14548061; -.
DR MassIVE; Q9BZS1; -.
DR MaxQB; Q9BZS1; -.
DR PaxDb; Q9BZS1; -.
DR PeptideAtlas; Q9BZS1; -.
DR PRIDE; Q9BZS1; -.
DR ProteomicsDB; 7545; -.
DR ProteomicsDB; 79899; -. [Q9BZS1-1]
DR ProteomicsDB; 79900; -. [Q9BZS1-2]
DR ProteomicsDB; 79901; -. [Q9BZS1-3]
DR TopDownProteomics; Q9BZS1-3; -. [Q9BZS1-3]
DR Antibodypedia; 485; 1954 antibodies from 53 providers.
DR DNASU; 50943; -.
DR Ensembl; ENST00000376199.7; ENSP00000365372.2; ENSG00000049768.17. [Q9BZS1-2]
DR Ensembl; ENST00000376207.10; ENSP00000365380.4; ENSG00000049768.17. [Q9BZS1-1]
DR Ensembl; ENST00000518685.6; ENSP00000428952.2; ENSG00000049768.17. [Q9BZS1-4]
DR Ensembl; ENST00000557224.6; ENSP00000451208.1; ENSG00000049768.17. [Q9BZS1-3]
DR GeneID; 50943; -.
DR KEGG; hsa:50943; -.
DR MANE-Select; ENST00000376207.10; ENSP00000365380.4; NM_014009.4; NP_054728.2.
DR UCSC; uc004dne.5; human. [Q9BZS1-1]
DR CTD; 50943; -.
DR DisGeNET; 50943; -.
DR GeneCards; FOXP3; -.
DR GeneReviews; FOXP3; -.
DR HGNC; HGNC:6106; FOXP3.
DR HPA; ENSG00000049768; Tissue enhanced (epididymis, lymphoid tissue).
DR MalaCards; FOXP3; -.
DR MIM; 300292; gene.
DR MIM; 304790; phenotype.
DR neXtProt; NX_Q9BZS1; -.
DR OpenTargets; ENSG00000049768; -.
DR Orphanet; 37042; Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome.
DR PharmGKB; PA201094; -.
DR VEuPathDB; HostDB:ENSG00000049768; -.
DR eggNOG; KOG4385; Eukaryota.
DR GeneTree; ENSGT00940000161807; -.
DR InParanoid; Q9BZS1; -.
DR OMA; HCQVDHL; -.
DR OrthoDB; 836427at2759; -.
DR PhylomeDB; Q9BZS1; -.
DR TreeFam; TF326978; -.
DR PathwayCommons; Q9BZS1; -.
DR Reactome; R-HSA-8877330; RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs).
DR Reactome; R-HSA-8939256; RUNX1 regulates transcription of genes involved in WNT signaling.
DR SignaLink; Q9BZS1; -.
DR SIGNOR; Q9BZS1; -.
DR BioGRID-ORCS; 50943; 13 hits in 721 CRISPR screens.
DR EvolutionaryTrace; Q9BZS1; -.
DR GeneWiki; FOXP3; -.
DR GenomeRNAi; 50943; -.
DR Pharos; Q9BZS1; Tbio.
DR PRO; PR:Q9BZS1; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; Q9BZS1; protein.
DR Bgee; ENSG00000049768; Expressed in tendon of biceps brachii and 136 other tissues.
DR ExpressionAtlas; Q9BZS1; baseline and differential.
DR Genevisible; Q9BZS1; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; NAS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IMP:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0035035; F:histone acetyltransferase binding; IPI:BHF-UCL.
DR GO; GO:0042826; F:histone deacetylase binding; IPI:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0051059; F:NF-kappaB binding; NAS:UniProtKB.
DR GO; GO:0051525; F:NFAT protein binding; IPI:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0003714; F:transcription corepressor activity; IEA:Ensembl.
DR GO; GO:0001782; P:B cell homeostasis; IEA:Ensembl.
DR GO; GO:0035739; P:CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl.
DR GO; GO:0002362; P:CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment; TAS:UniProtKB.
DR GO; GO:0006338; P:chromatin remodeling; NAS:UniProtKB.
DR GO; GO:0014045; P:establishment of endothelial blood-brain barrier; IEA:Ensembl.
DR GO; GO:0016573; P:histone acetylation; IEA:Ensembl.
DR GO; GO:0033080; P:immature T cell proliferation in thymus; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0048289; P:isotype switching to IgE isotypes; IEA:Ensembl.
DR GO; GO:0002262; P:myeloid cell homeostasis; IEA:Ensembl.
DR GO; GO:0046007; P:negative regulation of activated T cell proliferation; NAS:UniProtKB.
DR GO; GO:2000562; P:negative regulation of CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB.
DR GO; GO:0002677; P:negative regulation of chronic inflammatory response; IEA:Ensembl.
DR GO; GO:0032792; P:negative regulation of CREB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0001818; P:negative regulation of cytokine production; IDA:UniProtKB.
DR GO; GO:0050687; P:negative regulation of defense response to virus; IEA:Ensembl.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0035067; P:negative regulation of histone acetylation; IEA:Ensembl.
DR GO; GO:0031064; P:negative regulation of histone deacetylation; IGI:BHF-UCL.
DR GO; GO:0050777; P:negative regulation of immune response; IDA:UniProtKB.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; IDA:UniProtKB.
DR GO; GO:0032693; P:negative regulation of interleukin-10 production; IDA:UniProtKB.
DR GO; GO:0032700; P:negative regulation of interleukin-17 production; IMP:UniProtKB.
DR GO; GO:0032703; P:negative regulation of interleukin-2 production; IDA:UniProtKB.
DR GO; GO:0032713; P:negative regulation of interleukin-4 production; IDA:UniProtKB.
DR GO; GO:0032714; P:negative regulation of interleukin-5 production; IEA:Ensembl.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0048294; P:negative regulation of isotype switching to IgE isotypes; IEA:Ensembl.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0002725; P:negative regulation of T cell cytokine production; IDA:UniProtKB.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IDA:UniProtKB.
DR GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; IMP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0032831; P:positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation; TAS:UniProtKB.
DR GO; GO:0035066; P:positive regulation of histone acetylation; IMP:BHF-UCL.
DR GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; IEA:Ensembl.
DR GO; GO:0032753; P:positive regulation of interleukin-4 production; IEA:Ensembl.
DR GO; GO:0002851; P:positive regulation of peripheral T cell tolerance induction; IEA:Ensembl.
DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; IDA:UniProtKB.
DR GO; GO:0002669; P:positive regulation of T cell anergy; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0032914; P:positive regulation of transforming growth factor beta1 production; IEA:Ensembl.
DR GO; GO:0048302; P:regulation of isotype switching to IgG isotypes; IEA:Ensembl.
DR GO; GO:0002667; P:regulation of T cell anergy; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; NAS:UniProtKB.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR GO; GO:1901355; P:response to rapamycin; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0042110; P:T cell activation; IDA:UniProtKB.
DR GO; GO:0002870; P:T cell anergy; IEA:Ensembl.
DR GO; GO:0043029; P:T cell homeostasis; NAS:UniProtKB.
DR GO; GO:0002456; P:T cell mediated immunity; IEA:Ensembl.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0002513; P:tolerance induction to self antigen; IEA:Ensembl.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0032905; P:transforming growth factor beta1 production; IEA:Ensembl.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR IDEAL; IID00497; -.
DR InterPro; IPR001766; Fork_head_dom.
DR InterPro; IPR032354; FOXP-CC.
DR InterPro; IPR030456; TF_fork_head_CS_2.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR InterPro; IPR013087; Znf_C2H2_type.
DR Pfam; PF00250; Forkhead; 1.
DR Pfam; PF16159; FOXP-CC; 1.
DR PRINTS; PR00053; FORKHEAD.
DR SMART; SM00339; FH; 1.
DR SUPFAM; SSF46785; SSF46785; 1.
DR PROSITE; PS00658; FORK_HEAD_2; 1.
DR PROSITE; PS50039; FORK_HEAD_3; 1.
DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Alternative splicing; Cytoplasm;
KW Diabetes mellitus; Disease variant; DNA-binding; Isopeptide bond;
KW Metal-binding; Nucleus; Phosphoprotein; Reference proteome; Repressor;
KW Transcription; Transcription regulation; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1..431
FT /note="Forkhead box protein P3"
FT /id="PRO_0000091886"
FT CHAIN 1..417
FT /note="Forkhead box protein P3, C-terminally processed"
FT /evidence="ECO:0000305|PubMed:19117830"
FT /id="PRO_0000432430"
FT CHAIN 52..417
FT /note="Forkhead box protein P3 41 kDa form"
FT /evidence="ECO:0000305|PubMed:19117830"
FT /id="PRO_0000432431"
FT PROPEP 418..431
FT /evidence="ECO:0000305|PubMed:19117830"
FT /id="PRO_0000432432"
FT ZN_FING 197..222
FT /note="C2H2-type"
FT DNA_BIND 337..423
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..68
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 106..198
FT /note="Interaction with ZFP90"
FT /evidence="ECO:0000269|PubMed:23543754"
FT REGION 106..190
FT /note="Essential for transcriptional repressor activity and
FT for interaction with KAT5 and HDAC7"
FT /evidence="ECO:0000269|PubMed:17360565"
FT REGION 149..199
FT /note="Interaction with IKZF4"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT REGION 239..260
FT /note="Leucine-zipper"
FT REGION 278..336
FT /note="Interaction with RUNX1"
FT /evidence="ECO:0000269|PubMed:17377532"
FT MOTIF 68..76
FT /note="Nuclear export signal"
FT /evidence="ECO:0000269|PubMed:22678915"
FT MOTIF 92..96
FT /note="LXXLL motif"
FT /evidence="ECO:0000269|PubMed:18354202"
FT MOTIF 239..248
FT /note="Nuclear export signal"
FT /evidence="ECO:0000269|PubMed:22678915"
FT MOTIF 414..417
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:22678915"
FT COMPBIAS 53..67
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 51..52
FT /note="Cleavage"
FT /evidence="ECO:0000269|PubMed:19117830"
FT SITE 417..418
FT /note="Cleavage; by PCSK1 or PCSK2"
FT /evidence="ECO:0000269|PubMed:19117830"
FT MOD_RES 19
FT /note="Phosphoserine; by CDK2"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT MOD_RES 31
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:22312127"
FT MOD_RES 263
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000269|PubMed:22312127"
FT MOD_RES 268
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000269|PubMed:22312127"
FT MOD_RES 418
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23396208"
FT CROSSLNK 250
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT CROSSLNK 252
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT CROSSLNK 263
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT CROSSLNK 268
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT CROSSLNK 393
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT VAR_SEQ 72..106
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4,
FT ECO:0000303|Ref.7"
FT /id="VSP_015796"
FT VAR_SEQ 246..272
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_047859"
FT VAR_SEQ 382
FT /note="K -> KVSSSEVAVTGMASSAIAAQSGQAWVWAHRHIGEERDVGCWWWLLAS
FT EVDAHLLPVPGLPQ (in isoform 3)"
FT /evidence="ECO:0000303|Ref.7"
FT /id="VSP_036418"
FT VARIANT 242
FT /note="L -> P (in IPEX; mild phenotype; no loss of protein
FT expression)"
FT /evidence="ECO:0000269|PubMed:18951619"
FT /id="VAR_078971"
FT VARIANT 251
FT /note="Missing (in IPEX; significantly reduces
FT dimerization; dbSNP:rs122467171)"
FT /evidence="ECO:0000269|PubMed:11120765,
FT ECO:0000269|PubMed:21458306"
FT /id="VAR_011330"
FT VARIANT 324
FT /note="F -> L (in IPEX; mild phenotype; no loss of protein
FT expression; dbSNP:rs122467173)"
FT /evidence="ECO:0000269|PubMed:18951619"
FT /id="VAR_078972"
FT VARIANT 339
FT /note="P -> A (in IPEX; no loss of protein expression;
FT dbSNP:rs886044787)"
FT /evidence="ECO:0000269|PubMed:18951619"
FT /id="VAR_078973"
FT VARIANT 347
FT /note="R -> H (in IPEX; mild phenotype; no loss of protein
FT expression; impairs its ability to confer inhibitory
FT function to regulatory T-cells; no loss of DNA-binding when
FT associated with A-373; dbSNP:rs1557115786)"
FT /evidence="ECO:0000269|PubMed:18951619,
FT ECO:0000269|PubMed:21458306"
FT /id="VAR_078974"
FT VARIANT 363
FT /note="I -> V (in IPEX)"
FT /evidence="ECO:0000269|PubMed:11768393"
FT /id="VAR_023569"
FT VARIANT 371
FT /note="F -> C (in IPEX; no effect on dimerization;
FT dbSNP:rs122467169)"
FT /evidence="ECO:0000269|PubMed:11137992,
FT ECO:0000269|PubMed:21458306"
FT /id="VAR_011331"
FT VARIANT 373
FT /note="F -> A (in IPEX; requires 2 nucleotide
FT substitutions; no loss of protein expression; disrupts
FT dimerization; impairs its ability to confer inhibitory
FT function to regulatory T-cells; no loss of DNA-binding when
FT associated with H-347; dbSNP:rs122467172)"
FT /evidence="ECO:0000269|PubMed:18951619,
FT ECO:0000269|PubMed:21458306"
FT /id="VAR_078975"
FT VARIANT 374
FT /note="F -> C (in IPEX; no loss of protein expression)"
FT /evidence="ECO:0000269|PubMed:18951619"
FT /id="VAR_078976"
FT VARIANT 384
FT /note="A -> T (in IPEX; no loss of protein expression;
FT dbSNP:rs122467170)"
FT /evidence="ECO:0000269|PubMed:11137992,
FT ECO:0000269|PubMed:11137993, ECO:0000269|PubMed:18951619"
FT /id="VAR_011332"
FT VARIANT 397
FT /note="R -> W (in IPEX; dbSNP:rs28935477)"
FT /evidence="ECO:0000269|PubMed:11137992"
FT /id="VAR_011333"
FT MUTAGEN 69
FT /note="L->A: Decrease in nuclear export; when associated
FT with A-71, A-74 and A-76."
FT /evidence="ECO:0000269|PubMed:22678915"
FT MUTAGEN 71
FT /note="L->A: Decrease in nuclear export; when associated
FT with A-69, A-74 and A-76."
FT /evidence="ECO:0000269|PubMed:22678915"
FT MUTAGEN 74
FT /note="L->A: Decrease in nuclear export; when associated
FT with A-69, A-71 and A-76."
FT /evidence="ECO:0000269|PubMed:22678915"
FT MUTAGEN 76
FT /note="L->A: Decrease in nuclear export; when associated
FT with A-69, A-71 and A-74."
FT /evidence="ECO:0000269|PubMed:22678915"
FT MUTAGEN 95..96
FT /note="LL->AA: Loss of interaction with RORA."
FT /evidence="ECO:0000269|PubMed:18354202"
FT MUTAGEN 242
FT /note="L->A: Decrease in nuclear export; when associated
FT with A-246 and A-248."
FT /evidence="ECO:0000269|PubMed:22678915"
FT MUTAGEN 246
FT /note="L->A: Decrease in nuclear export; when associated
FT with A-242 and A-248."
FT /evidence="ECO:0000269|PubMed:22678915"
FT MUTAGEN 248
FT /note="L->A: Decrease in nuclear export; when associated
FT with A-242 and A-246."
FT /evidence="ECO:0000269|PubMed:22678915"
FT MUTAGEN 348
FT /note="W->Q: No loss of DNA-binding. Disrupts dimerization
FT but does not affect DNA-binding; when associated with T-
FT 370. Disrupts dimerization, does not affect DNA-binding,
FT causes dysregulated expression of a subset of FOXP3 target
FT genes and impairs its ability to confer inhibitory function
FT to regulatory T-cells; when associated with T-370 and P-
FT 372."
FT /evidence="ECO:0000269|PubMed:21458306"
FT MUTAGEN 370
FT /note="M->T: Disrupts dimerization but does not affect DNA-
FT binding; when associated with Q-348. Disrupts dimerization,
FT does not affect DNA-binding, causes dysregulated expression
FT of a subset of FOXP3 target genes and impairs its ability
FT to confer inhibitory function to regulatory T-cells; when
FT associated with Q-348 and P-372."
FT /evidence="ECO:0000269|PubMed:21458306"
FT MUTAGEN 372
FT /note="A->P: Disrupts dimerization, does not affect DNA-
FT binding, causes dysregulated expression of a subset of
FT FOXP3 target genes and impairs its ability to confer
FT inhibitory function to regulatory T-cells; when associated
FT with Q-348 and T-370."
FT /evidence="ECO:0000269|PubMed:21458306"
FT MUTAGEN 415..416
FT /note="KK->EE: Loss of nuclear localization."
FT /evidence="ECO:0000269|PubMed:22678915"
FT MUTAGEN 418
FT /note="S->A: Decrease in phosphorylation, significant
FT decrease in transcriptional repressor activity and reduced
FT interaction with PP1CA, PP1CB and PP1CG. Significant
FT decrease in phosphorylation and transcriptional repressor
FT activity; when associated with A-422."
FT /evidence="ECO:0000269|PubMed:23396208"
FT MUTAGEN 418
FT /note="S->E: Slight increase in transcriptional repressor
FT activity."
FT /evidence="ECO:0000269|PubMed:23396208"
FT MUTAGEN 422
FT /note="S->A: Significant decrease in phosphorylation and
FT transcriptional repressor activity; when associated with A-
FT 418."
FT /evidence="ECO:0000269|PubMed:23396208"
FT CONFLICT 16..20
FT /note="LGPSP -> MSPIS (in Ref. 7; CAA06748)"
FT /evidence="ECO:0000305"
FT HELIX 342..351
FT /evidence="ECO:0007829|PDB:3QRF"
FT HELIX 360..371
FT /evidence="ECO:0007829|PDB:3QRF"
FT TURN 372..375
FT /evidence="ECO:0007829|PDB:3QRF"
FT HELIX 381..391
FT /evidence="ECO:0007829|PDB:3QRF"
FT STRAND 395..398
FT /evidence="ECO:0007829|PDB:3QRF"
FT STRAND 401..403
FT /evidence="ECO:0007829|PDB:3QRF"
FT STRAND 405..408
FT /evidence="ECO:0007829|PDB:3QRF"
FT HELIX 410..416
FT /evidence="ECO:0007829|PDB:3QRF"
SQ SEQUENCE 431 AA; 47244 MW; 91737C3CEA665A15 CRC64;
MPNPRPGKPS APSLALGPSP GASPSWRAAP KASDLLGARG PGGTFQGRDL RGGAHASSSS
LNPMPPSQLQ LPTLPLVMVA PSGARLGPLP HLQALLQDRP HFMHQLSTVD AHARTPVLQV
HPLESPAMIS LTPPTTATGV FSLKARPGLP PGINVASLEW VSREPALLCT FPNPSAPRKD
STLSAVPQSS YPLLANGVCK WPGCEKVFEE PEDFLKHCQA DHLLDEKGRA QCLLQREMVQ
SLEQQLVLEK EKLSAMQAHL AGKMALTKAS SVASSDKGSC CIVAAGSQGP VVPAWSGPRE
APDSLFAVRR HLWGSHGNST FPEFLHNMDY FKFHNMRPPF TYATLIRWAI LEAPEKQRTL
NEIYHWFTRM FAFFRNHPAT WKNAIRHNLS LHKCFVRVES EKGAVWTVDE LEFRKKRSQR
PSRCSNPTPG P
