FOXP3_MOUSE
ID FOXP3_MOUSE Reviewed; 429 AA.
AC Q99JB6;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 178.
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;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
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 FUNCTION.
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 [3]
RP HOMODIMERIZATION, AND MUTAGENESIS OF GLU-250.
RX PubMed=16769892; DOI=10.1073/pnas.0600225103;
RA Chae W.J., Henegariu O., Lee S.K., Bothwell A.L.;
RT "The mutant leucine-zipper domain impairs both dimerization and suppressive
RT function of Foxp3 in T cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:9631-9636(2006).
RN [4]
RP FUNCTION, INTERACTION WITH RUNX1; RUNX2; RUNX3 AND NFATC2, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF 329-ASP-TYR-330 AND LYS-332.
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 [5]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RORC, AND INDUCTION.
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 [6]
RP PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 48-ARG--ARG-51 AND 414-ARG--ARG-417.
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 [7]
RP FUNCTION, AND INTERACTION WITH IKZF4; HDAC7 AND KAT5.
RX PubMed=19696312; DOI=10.1126/science.1176077;
RA Pan F., Yu H., Dang E.V., Barbi J., Pan X., Grosso J.F., Jinasena D.,
RA Sharma S.M., McCadden E.M., Getnet D., Drake C.G., Liu J.O.,
RA Ostrowski M.C., Pardoll D.M.;
RT "Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells.";
RL Science 325:1142-1146(2009).
RN [8]
RP ACETYLATION AT LYS-31; LYS-262 AND LYS-267, 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 [9]
RP UBIQUITINATION AT LYS-249; LYS-251; LYS-262; LYS-267 AND LYS-393, AND
RP DEUBIQUITINATION.
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 [10]
RP UBIQUITINATION, INTERACTION WITH STUB1 AND HSPA1A/B, 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 [11]
RP PHOSPHORYLATION AT SER-19 AND THR-175, AND MUTAGENESIS OF SER-19; SER-88;
RP THR-114 AND THR-175.
RX PubMed=23853094; DOI=10.1074/jbc.m113.467704;
RA Morawski P.A., Mehra P., Chen C., Bhatti T., Wells A.D.;
RT "Foxp3 protein stability is regulated by cyclin-dependent kinase 2.";
RL J. Biol. Chem. 288:24494-24502(2013).
RN [12]
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).
CC -!- FUNCTION: Transcriptional regulator which is crucial for the
CC development and inhibitory function of regulatory T-cells (Treg). Plays
CC an essential role in maintaining homeostasis of the immune system by
CC allowing the acquisition of full suppressive function and stability of
CC the Treg lineage, and by directly modulating the expansion and function
CC of conventional T-cells. Can act either as a transcriptional repressor
CC or a transcriptional activator depending on its interactions with other
CC transcription factors, histone acetylases and deacetylases. The
CC suppressive activity of Treg involves the coordinate activation of many
CC genes, including CTLA4 and TNFRSF18 by FOXP3 along with repression of
CC genes encoding cytokines such as interleukin-2 (IL2) and interferon-
CC gamma (IFNG). Inhibits cytokine production and T-cell effector function
CC by repressing the activity of two key transcription factors, RELA and
CC NFATC2 (PubMed:15790681). Mediates transcriptional repression of IL2
CC via its association with histone acetylase KAT5 and histone deacetylase
CC HDAC7 (By similarity). Can activate the expression of TNFRSF18, IL2RA
CC and CTLA4 and repress the expression of IL2 and IFNG via its
CC association with transcription factor RUNX1 (PubMed:17377532). Inhibits
CC 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 (By similarity). Can repress
CC the expression of IL2 and IFNG via its association with transcription
CC factor IKZF4 (PubMed:19696312). {ECO:0000250|UniProtKB:Q9BZS1,
CC ECO:0000269|PubMed:15790681, ECO:0000269|PubMed:17377532,
CC ECO:0000269|PubMed:18368049, ECO:0000269|PubMed:19696312}.
CC -!- SUBUNIT: Homodimer. Dimerization is essential for its transcriptional
CC regulator activity. Interacts with IKZF3 (By similarity). Interacts
CC (via LXXLL motif) with isoform 4 of RORA (via AF-2 motif) (By
CC similarity). Interacts with STUB1 and HSPA1A/B. Interacts with IKZF4,
CC HDAC7 and KAT5. Interacts with RUNX1, RUNX2, RUNX3 and NFATC2.
CC Interacts with RORC. Interacts with HDAC9 in the absence of T-cell
CC stimulation (By similarity). Interacts with RELA, PPP1CA, PPP1CB,
CC PPP1CG, HSPA8 and USP7 (By similarity). {ECO:0000250|UniProtKB:Q9BZS1,
CC ECO:0000269|PubMed:16769892, ECO:0000269|PubMed:17377532,
CC ECO:0000269|PubMed:18368049, ECO:0000269|PubMed:19696312,
CC ECO:0000269|PubMed:23973223}.
CC -!- INTERACTION:
CC Q99JB6; Q03347: Runx1; NbExp=5; IntAct=EBI-10956246, EBI-3863873;
CC Q99JB6; Q8C2S0: Usp44; NbExp=3; IntAct=EBI-10956246, EBI-26303241;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00089,
CC ECO:0000269|PubMed:17377532, ECO:0000269|PubMed:18368049}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9BZS1}. Note=Predominantly expressed in the
CC cytoplasm in activated conventional T-cells whereas predominantly
CC expressed in the nucleus in regulatory T-cells (Treg) (By similarity).
CC The 41 kDa form derived by proteolytic processing is found exclusively
CC in the chromatin fraction of activated Treg cells.
CC {ECO:0000250|UniProtKB:Q9BZS1, ECO:0000269|PubMed:19117830}.
CC -!- TISSUE SPECIFICITY: High level of expression in thymus and spleen.
CC -!- INDUCTION: By TGFB1 in T-cells. Down-regulated in regulatory T-cells
CC (Treg) during inflammation. {ECO:0000269|PubMed:18368049,
CC ECO:0000269|PubMed:23973223}.
CC -!- DOMAIN: The fork-head DNA-binding domain is essential for its
CC dimerization and interaction with NFATC2.
CC {ECO:0000250|UniProtKB:Q9BZS1}.
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:22312127). Acetylation is
CC mediated by a coordinated action of KAT5 and EP300/p300
CC acetyltransferases: EP300/p300 is required to enhance KAT5
CC autoacetylation, promoting acetylation of FOXP3 by KAT5 (By
CC similarity). Deacetylated by SIRT1 (PubMed:22312127).
CC {ECO:0000250|UniProtKB:Q9BZS1, ECO:0000269|PubMed:22312127}.
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 (By similarity). Phosphorylation by CDK2 negatively regulates
CC its transcriptional activity and protein stability.
CC {ECO:0000250|UniProtKB:Q9BZS1, ECO:0000269|PubMed:23853094}.
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. Treg expressing the form cleaved at C-terminal site or both
CC N- and C-terminal sites exhibit an increased induction of IL10 and an
CC increased capacity to suppress proliferation of conventional T-cells in
CC vitro. Treg expressing the form cleaved at only the C-terminal site are
CC highly effective at preventing experimental colitis in an in vivo model
CC of inflammatory bowel disease. {ECO:0000269|PubMed:19117830}.
CC -!- DISEASE: Note=Defects in Foxp3 are the cause of the scurfy phenotype
CC (sf). It results in a lethal disorder of immunoregulation,
CC characterized by infections, diarrhea, anemia, thrombocytopenia,
CC hypogonadism, gastrointestinal bleeding, lymphadenopathy and
CC leukocytosis.
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DR EMBL; AF277994; AAG53608.1; -; Genomic_DNA.
DR EMBL; AF277991; AAG53605.1; -; mRNA.
DR EMBL; AF277992; AAG53606.1; -; mRNA.
DR CCDS; CCDS29965.1; -.
DR RefSeq; NP_001186276.1; NM_001199347.1.
DR RefSeq; NP_001186277.1; NM_001199348.1.
DR RefSeq; NP_473380.1; NM_054039.2.
DR PDB; 4I1L; X-ray; 2.10 A; A=189-276.
DR PDBsum; 4I1L; -.
DR AlphaFoldDB; Q99JB6; -.
DR SMR; Q99JB6; -.
DR BioGRID; 203183; 371.
DR DIP; DIP-59739N; -.
DR IntAct; Q99JB6; 14.
DR MINT; Q99JB6; -.
DR STRING; 10090.ENSMUSP00000111405; -.
DR iPTMnet; Q99JB6; -.
DR PhosphoSitePlus; Q99JB6; -.
DR PaxDb; Q99JB6; -.
DR PRIDE; Q99JB6; -.
DR ProteomicsDB; 267500; -.
DR Antibodypedia; 485; 1954 antibodies from 53 providers.
DR DNASU; 20371; -.
DR Ensembl; ENSMUST00000045566; ENSMUSP00000041953; ENSMUSG00000039521.
DR Ensembl; ENSMUST00000115738; ENSMUSP00000111403; ENSMUSG00000039521.
DR Ensembl; ENSMUST00000115739; ENSMUSP00000111404; ENSMUSG00000039521.
DR Ensembl; ENSMUST00000115740; ENSMUSP00000111405; ENSMUSG00000039521.
DR Ensembl; ENSMUST00000234363; ENSMUSP00000157093; ENSMUSG00000039521.
DR Ensembl; ENSMUST00000235116; ENSMUSP00000157059; ENSMUSG00000039521.
DR GeneID; 20371; -.
DR KEGG; mmu:20371; -.
DR UCSC; uc009sll.2; mouse.
DR CTD; 50943; -.
DR MGI; MGI:1891436; Foxp3.
DR VEuPathDB; HostDB:ENSMUSG00000039521; -.
DR eggNOG; KOG4385; Eukaryota.
DR GeneTree; ENSGT00940000161807; -.
DR HOGENOM; CLU_019502_1_0_1; -.
DR InParanoid; Q99JB6; -.
DR OMA; HCQVDHL; -.
DR OrthoDB; 836427at2759; -.
DR PhylomeDB; Q99JB6; -.
DR TreeFam; TF326978; -.
DR Reactome; R-MMU-8877330; RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs).
DR BioGRID-ORCS; 20371; 5 hits in 116 CRISPR screens.
DR PRO; PR:Q99JB6; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; Q99JB6; protein.
DR Bgee; ENSMUSG00000039521; Expressed in urethra and 51 other tissues.
DR ExpressionAtlas; Q99JB6; baseline and differential.
DR Genevisible; Q99JB6; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISO:MGI.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:MGI.
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; ISO:MGI.
DR GO; GO:0042826; F:histone deacetylase binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; IPI:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0051525; F:NFAT protein binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:MGI.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0003714; F:transcription corepressor activity; IDA:MGI.
DR GO; GO:0046633; P:alpha-beta T cell proliferation; IMP:MGI.
DR GO; GO:0001782; P:B cell homeostasis; IMP:MGI.
DR GO; GO:0043367; P:CD4-positive, alpha-beta T cell differentiation; IDA:MGI.
DR GO; GO:0035739; P:CD4-positive, alpha-beta T cell proliferation; IDA:MGI.
DR GO; GO:0002361; P:CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation; IMP:MGI.
DR GO; GO:0002362; P:CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment; TAS:UniProtKB.
DR GO; GO:0014045; P:establishment of endothelial blood-brain barrier; IEA:Ensembl.
DR GO; GO:0010467; P:gene expression; IMP:MGI.
DR GO; GO:0016573; P:histone acetylation; IDA:MGI.
DR GO; GO:0033080; P:immature T cell proliferation in thymus; IMP:MGI.
DR GO; GO:0006954; P:inflammatory response; IMP:MGI.
DR GO; GO:0048289; P:isotype switching to IgE isotypes; IMP:MGI.
DR GO; GO:0046651; P:lymphocyte proliferation; IMP:MGI.
DR GO; GO:0002262; P:myeloid cell homeostasis; IMP:MGI.
DR GO; GO:0046642; P:negative regulation of alpha-beta T cell proliferation; IMP:MGI.
DR GO; GO:2000562; P:negative regulation of CD4-positive, alpha-beta T cell proliferation; IDA:MGI.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0002677; P:negative regulation of chronic inflammatory response; IDA:MGI.
DR GO; GO:0032792; P:negative regulation of CREB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0001818; P:negative regulation of cytokine production; ISS:UniProtKB.
DR GO; GO:0050687; P:negative regulation of defense response to virus; ISO:MGI.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IDA:MGI.
DR GO; GO:0035067; P:negative regulation of histone acetylation; IDA:MGI.
DR GO; GO:0031064; P:negative regulation of histone deacetylation; ISO:MGI.
DR GO; GO:0050777; P:negative regulation of immune response; ISS:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:MGI.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; IDA:UniProtKB.
DR GO; GO:0032693; P:negative regulation of interleukin-10 production; IMP:MGI.
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:MGI.
DR GO; GO:0032714; P:negative regulation of interleukin-5 production; IDA:MGI.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IMP:MGI.
DR GO; GO:0048294; P:negative regulation of isotype switching to IgE isotypes; IMP:MGI.
DR GO; GO:0050672; P:negative regulation of lymphocyte proliferation; IMP:MGI.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0002725; P:negative regulation of T cell cytokine production; ISS:UniProtKB.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IDA:MGI.
DR GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IMP:MGI.
DR GO; GO:0043372; P:positive regulation of CD4-positive, alpha-beta T cell differentiation; IDA:MGI.
DR GO; GO:0032831; P:positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation; IMP:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:MGI.
DR GO; GO:0035066; P:positive regulation of histone acetylation; IDA:MGI.
DR GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; IMP:MGI.
DR GO; GO:0032753; P:positive regulation of interleukin-4 production; IMP:MGI.
DR GO; GO:0002851; P:positive regulation of peripheral T cell tolerance induction; IMP:MGI.
DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; IDA:MGI.
DR GO; GO:0002669; P:positive regulation of T cell anergy; IMP:MGI.
DR GO; GO:0002666; P:positive regulation of T cell tolerance induction; IMP:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0032914; P:positive regulation of transforming growth factor beta1 production; IDA:MGI.
DR GO; GO:0002637; P:regulation of immunoglobulin production; IMP:MGI.
DR GO; GO:0048302; P:regulation of isotype switching to IgG isotypes; IMP:MGI.
DR GO; GO:0002667; P:regulation of T cell anergy; IMP:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IGI:MGI.
DR GO; GO:0045066; P:regulatory T cell differentiation; IDA:MGI.
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; IEA:Ensembl.
DR GO; GO:0042110; P:T cell activation; IMP:MGI.
DR GO; GO:0002870; P:T cell anergy; IMP:MGI.
DR GO; GO:0002456; P:T cell mediated immunity; IMP:MGI.
DR GO; GO:0042098; P:T cell proliferation; IDA:MGI.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IMP:MGI.
DR GO; GO:0002517; P:T cell tolerance induction; IMP:MGI.
DR GO; GO:0002507; P:tolerance induction; IDA:MGI.
DR GO; GO:0002513; P:tolerance induction to self antigen; IMP:MGI.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0006351; P:transcription, DNA-templated; IDA:MGI.
DR GO; GO:0032905; P:transforming growth factor beta1 production; IDA:MGI.
DR CDD; cd00059; FH; 1.
DR Gene3D; 1.10.10.10; -; 1.
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; Cytoplasm; DNA-binding;
KW Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Repressor; Transcription; Transcription regulation;
KW Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..429
FT /note="Forkhead box protein P3"
FT /id="PRO_0000091888"
FT CHAIN 1..417
FT /note="Forkhead box protein P3, C-terminally processed"
FT /evidence="ECO:0000305|PubMed:19117830"
FT /id="PRO_0000432436"
FT CHAIN 52..417
FT /note="Forkhead box protein P3 41 kDa form"
FT /evidence="ECO:0000305|PubMed:19117830"
FT /id="PRO_0000432437"
FT PROPEP 418..429
FT /evidence="ECO:0000305|PubMed:19117830"
FT /id="PRO_0000432438"
FT ZN_FING 196..221
FT /note="C2H2-type"
FT DNA_BIND 337..423
FT /note="Fork-head"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00089"
FT REGION 1..67
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 105..189
FT /note="Essential for transcriptional repressor activity and
FT for interaction with KAT5 and HDAC7"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT REGION 148..198
FT /note="Interaction with IKZF4"
FT /evidence="ECO:0000269|PubMed:19696312"
FT REGION 238..259
FT /note="Leucine-zipper"
FT REGION 277..336
FT /note="Interaction with RUNX1"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT MOTIF 67..75
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT MOTIF 91..95
FT /note="LXXLL motif"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT MOTIF 238..247
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT MOTIF 414..417
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT COMPBIAS 51..66
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:0000269|PubMed:23853094"
FT MOD_RES 31
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:22312127"
FT MOD_RES 175
FT /note="Phosphothreonine; by CDK2"
FT /evidence="ECO:0000269|PubMed:23853094"
FT MOD_RES 262
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000269|PubMed:22312127"
FT MOD_RES 267
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000269|PubMed:22312127"
FT MOD_RES 418
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT CROSSLNK 249
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23973222"
FT CROSSLNK 251
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23973222"
FT CROSSLNK 262
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000269|PubMed:23973222"
FT CROSSLNK 267
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000269|PubMed:23973222"
FT CROSSLNK 393
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:23973222"
FT MUTAGEN 19
FT /note="S->A: Loss of phosphorylation. Increase in protein
FT stability, transcriptional activity and the ability to
FT suppress the proliferation of conventional T-cells in
FT vitro; when associated with A-88; A-114 and A-175."
FT /evidence="ECO:0000269|PubMed:23853094"
FT MUTAGEN 48..51
FT /note="RDLR->HDLH: Loss of proteolytic processing."
FT /evidence="ECO:0000269|PubMed:19117830"
FT MUTAGEN 88
FT /note="S->A: Increase in protein stability, transcriptional
FT activity and the ability to suppress the proliferation of
FT conventional T-cells in vitro; when associated with A-19;
FT A-114 and A-175."
FT /evidence="ECO:0000269|PubMed:23853094"
FT MUTAGEN 114
FT /note="T->A: Increase in protein stability, transcriptional
FT activity and the ability to suppress the proliferation of
FT conventional T-cells in vitro; when associated with A-19;
FT A-88 and A-175."
FT /evidence="ECO:0000269|PubMed:23853094"
FT MUTAGEN 175
FT /note="T->A: Increase in protein stability, transcriptional
FT activity and the ability to suppress the proliferation of
FT conventional T-cells in vitro; when associated with A-19;
FT A-88 and A-114."
FT /evidence="ECO:0000269|PubMed:23853094"
FT MUTAGEN 250
FT /note="Missing: Loss of homodimerization, decrease in
FT transcriptional repressor activity, elimination of its Treg
FT suppressor activity, defects in Th1 and Th2 cytokine
FT secretion and down-regulation of cell surface markers on
FT regulatory T-cells."
FT /evidence="ECO:0000269|PubMed:16769892"
FT MUTAGEN 329..330
FT /note="DY->VH: Reduced interaction with RUNX1, decrease in
FT its ability to regulate the expression of IL2, TNFRSF18,
FT IL2RA and CTLA4 in a RUNX1-dependent manner. Loss of
FT interaction with RUNX1 but no effect on interaction with
FT NFATC2 and loss of its ability to regulate the expression
FT of IL2, TNFRSF18, IL2RA and CTLA4 in a RUNX1-dependent
FT manner; when associated with L-332."
FT /evidence="ECO:0000269|PubMed:17377532"
FT MUTAGEN 332
FT /note="K->L: Loss of interaction with RUNX1 but no effect
FT on interaction with NFATC2 and loss of its ability to
FT regulate the expression of IL2, TNFRSF18, IL2RA and CTLA4
FT in a RUNX1-dependent manner; when associated with 329-VH-
FT 330."
FT /evidence="ECO:0000269|PubMed:17377532"
FT MUTAGEN 414..417
FT /note="RKKR->PNNW: Loss of ability to suppress the
FT proliferation of effector T-cells."
FT /evidence="ECO:0000269|PubMed:19117830"
FT MUTAGEN 414..417
FT /note="RKKR->QNKS: Loss of proteolytic processing."
FT /evidence="ECO:0000269|PubMed:19117830"
FT TURN 204..207
FT /evidence="ECO:0007829|PDB:4I1L"
FT HELIX 208..257
FT /evidence="ECO:0007829|PDB:4I1L"
SQ SEQUENCE 429 AA; 47346 MW; 28D5B8E67891840C CRC64;
MPNPRPAKPM APSLALGPSP GVLPSWKTAP KGSELLGTRG SGGPFQGRDL RSGAHTSSSL
NPLPPSQLQL PTVPLVMVAP SGARLGPSPH LQALLQDRPH FMHQLSTVDA HAQTPVLQVR
PLDNPAMISL PPPSAATGVF SLKARPGLPP GINVASLEWV SREPALLCTF PRSGTPRKDS
NLLAAPQGSY PLLANGVCKW PGCEKVFEEP EEFLKHCQAD HLLDEKGKAQ CLLQREVVQS
LEQQLELEKE KLGAMQAHLA GKMALAKAPS VASMDKSSCC IVATSTQGSV LPAWSAPREA
PDGGLFAVRR HLWGSHGNSS FPEFFHNMDY FKYHNMRPPF TYATLIRWAI LEAPERQRTL
NEIYHWFTRM FAYFRNHPAT WKNAIRHNLS LHKCFVRVES EKGAVWTVDE FEFRKKRSQR
PNKCSNPCP
