FOXP3_MACFA
ID FOXP3_MACFA Reviewed; 431 AA.
AC Q6U8D7;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 25-MAY-2022, entry version 95.
DE RecName: Full=Forkhead box protein P3;
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 Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Apoil P.-A., Tiraby G., Blancher A.;
RT "Transduction of macaque lymphocytes by Foxp3: in vitro functional
RT studies.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
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. Mediates transcriptional repression of IL2 via its association
CC with histone acetylase KAT5 and histone deacetylase HDAC7. Can activate
CC the expression of TNFRSF18, IL2RA and CTLA4 and repress the expression
CC of IL2 and IFNG via its association with transcription factor RUNX1.
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. Inhibits the transcriptional
CC activator activity of RORA (By similarity). Can repress the expression
CC of IL2 and IFNG via its association with transcription factor IKZF4 (By
CC similarity). {ECO:0000250|UniProtKB:Q99JB6,
CC ECO:0000250|UniProtKB:Q9BZS1}.
CC -!- SUBUNIT: Homodimer. Dimerization is essential for its transcriptional
CC regulator activity. Interacts with IKZF3. Interacts (via LXXLL motif)
CC with RORA (via AF-2 motif). Interacts with HDAC9 in the absence of T-
CC cell stimulation. Interacts with PPP1CA, PPP1CB, PPP1CG, KAT5, HDAC7,
CC HSPA8, USP7, STUB1, HSPA1A/B, RUNX1, RUNX2, RUNX3, RELA, NFATC2, IKFZ4
CC and RORC. {ECO:0000250|UniProtKB:Q99JB6, ECO:0000250|UniProtKB:Q9BZS1}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q9BZS1,
CC ECO:0000255|PROSITE-ProRule:PRU00089}. 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). The 41 kDa form
CC derived by proteolytic processing is found exclusively in the chromatin
CC fraction of activated Treg cells. {ECO:0000250|UniProtKB:Q99JB6,
CC ECO:0000250|UniProtKB:Q9BZS1}.
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: Phosphorylation at Ser-418 regulates its transcriptional repressor
CC activity and consequently, regulatory T-cells (Treg) suppressive
CC function. Phosphorylation by CDK2 negatively regulates its
CC transcriptional activity and protein stability.
CC {ECO:0000250|UniProtKB:Q99JB6, ECO:0000250|UniProtKB:Q9BZS1}.
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: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. Acetylation is mediated by a
CC coordinated action of KAT5 and EP300/p300 acetyltransferases:
CC EP300/p300 is required to enhance KAT5 autoacetylation, promoting
CC acetylation of FOXP3 by KAT5. Deacetylated by SIRT1.
CC {ECO:0000250|UniProtKB:Q9BZS1}.
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:0000250|UniProtKB:Q99JB6}.
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DR EMBL; AY376065; AAQ82647.1; -; mRNA.
DR AlphaFoldDB; Q6U8D7; -.
DR SMR; Q6U8D7; -.
DR STRING; 9541.XP_005593605.1; -.
DR eggNOG; KOG4385; Eukaryota.
DR Proteomes; UP000233100; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
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:0004674; F:protein serine/threonine kinase 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; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
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:0043433; P:negative regulation of DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0050777; P:negative regulation of immune response; ISS:UniProtKB.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; ISS:UniProtKB.
DR GO; GO:0032693; P:negative regulation of interleukin-10 production; ISS:UniProtKB.
DR GO; GO:0032703; P:negative regulation of interleukin-2 production; ISS:UniProtKB.
DR GO; GO:0032713; P:negative regulation of interleukin-4 production; ISS:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0045591; P:positive regulation of regulatory T cell differentiation; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0002667; P:regulation of T cell anergy; ISS:UniProtKB.
DR GO; GO:0042110; P:T cell activation; ISS:UniProtKB.
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 2: Evidence at transcript level;
KW Acetylation; Activator; Cytoplasm; 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_0000091887"
FT CHAIN 1..417
FT /note="Forkhead box protein P3, C-terminally processed"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT /id="PRO_0000432433"
FT CHAIN 52..417
FT /note="Forkhead box protein P3 41 kDa form"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT /id="PRO_0000432434"
FT PROPEP 418..431
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT /id="PRO_0000432435"
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..190
FT /note="Essential for transcriptional repressor activity and
FT for interaction with KAT5 and HDAC7"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
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:0000250|UniProtKB:Q9BZS1"
FT MOTIF 68..76
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT MOTIF 92..96
FT /note="LXXLL motif"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT MOTIF 239..248
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 53..67
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 51..52
FT /note="Cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
FT SITE 417..418
FT /note="Cleavage; by PCSK1 or PCSK2"
FT /evidence="ECO:0000250|UniProtKB:Q99JB6"
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:0000250|UniProtKB:Q9BZS1"
FT MOD_RES 263
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT MOD_RES 268
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
FT MOD_RES 418
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9BZS1"
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"
SQ SEQUENCE 431 AA; 47216 MW; 6C5F4AB342A9630F CRC64;
MPNPRPGKPS APSLALGPSP GASPSWRAAP KASDLLGARG PGGIFQGRDL RGGAHASSSS
LNPMPPSQLQ LPTLPLVMVA PSGARLGPLP HLQALLQDRP HFMHQLSTVD AHARTPVLQV
HPLESPAMIS LPPPTTATGV FSLKARPGLP PGINVASLEW VSREPALLCT FPNPGAPRKD
STLSAMPQSS YPLLANGVCK WPGCEKVFEE PEDFLKHCQA DHLLDEKGRA QCLLQREMVQ
SLEQQLVLEK EKLSAMQAHL AGKMALTKAS SVASSDKGSC CIVAAGSQGS AVPAWSGPRE
APDSLFAVRR HLWGSHGNST FPEFLHNMDY FKFHNMRPPF TYATLIRWAI LEAPEKQRTL
NEIYHWFTRM FAFFRNHPAT WKNAIRHNLS LHKCFVRVES EKGAVWTVDE LEFRKKRSQR
PSRCSNPTPG P
