TBX21_HUMAN
ID TBX21_HUMAN Reviewed; 535 AA.
AC Q9UL17;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=T-box transcription factor TBX21;
DE Short=T-box protein 21;
DE AltName: Full=T-cell-specific T-box transcription factor T-bet;
DE AltName: Full=Transcription factor TBLYM;
GN Name=TBX21; Synonyms=TBET, TBLYM;
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].
RA Yang S.;
RT "Cloning and characterization of a new member of T-box gene family.";
RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=10761931; DOI=10.1016/s0092-8674(00)80702-3;
RA Szabo S.J., Kim S.T., Costa G.L., Zhang X., Fathman C.G., Glimcher L.H.;
RT "A novel transcription factor, T-bet, directs Th1 lineage commitment.";
RL Cell 100:655-669(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 [4]
RP INVOLVEMENT IN ANPAI, AND VARIANT GLN-33.
RX PubMed=15806396; DOI=10.1007/s00439-005-1285-0;
RA Akahoshi M., Obara K., Hirota T., Matsuda A., Hasegawa K., Takahashi N.,
RA Shimizu M., Nakashima K., Cheng L., Doi S., Fujiwara H., Miyatake A.,
RA Fujita K., Higashi N., Taniguchi M., Enomoto T., Mao X.-Q., Nakashima H.,
RA Adra C.N., Nakamura Y., Tamari M., Shirakawa T.;
RT "Functional promoter polymorphism in the TBX21 gene associated with
RT aspirin-induced asthma.";
RL Hum. Genet. 117:16-26(2005).
RN [5]
RP INTERACTION WITH GATA3.
RX PubMed=15662016; DOI=10.1126/science.1103336;
RA Hwang E.S., Szabo S.J., Schwartzberg P.L., Glimcher L.H.;
RT "T helper cell fate specified by kinase-mediated interaction of T-bet with
RT GATA-3.";
RL Science 307:430-433(2005).
RN [6]
RP DEUBIQUITINATION, SUBCELLULAR LOCATION, AND INTERACTION WITH USP10.
RX PubMed=24845384; DOI=10.1016/j.bbrc.2014.05.037;
RA Pan L., Chen Z., Wang L., Chen C., Li D., Wan H., Li B., Shi G.;
RT "Deubiquitination and stabilization of T-bet by USP10.";
RL Biochem. Biophys. Res. Commun. 449:289-294(2014).
RN [7]
RP FUNCTION, AND INTERACTION WITH CCNT1.
RX PubMed=27292648; DOI=10.1016/j.celrep.2016.05.054;
RA Hertweck A., Evans C.M., Eskandarpour M., Lau J.C., Oleinika K.,
RA Jackson I., Kelly A., Ambrose J., Adamson P., Cousins D.J., Lavender P.,
RA Calder V.L., Lord G.M., Jenner R.G.;
RT "T-bet activates Th1 genes through mediator and the super elongation
RT complex.";
RL Cell Rep. 15:2756-2770(2016).
RN [8]
RP VARIANT IMD88 156-GLU-MET-157 DELINS SER-LEU, CHARACTERIZATION OF VARIANT
RP IMD88 156-GLU-MET-157 DELINS SER-LEU, INVOLVEMENT IN IMD88, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=33296702; DOI=10.1016/j.cell.2020.10.046;
RA Yang R., Mele F., Worley L., Langlais D., Rosain J., Benhsaien I.,
RA Elarabi H., Croft C.A., Doisne J.M., Zhang P., Weisshaar M., Jarrossay D.,
RA Latorre D., Shen Y., Han J., Ogishi M., Gruber C., Markle J., Al Ali F.,
RA Rahman M., Khan T., Seeleuthner Y., Kerner G., Husquin L.T., Maclsaac J.L.,
RA Jeljeli M., Errami A., Ailal F., Kobor M.S., Oleaga-Quintas C., Roynard M.,
RA Bourgey M., El Baghdadi J., Boisson-Dupuis S., Puel A., Batteux F.,
RA Rozenberg F., Marr N., Pan-Hammarstroem Q., Bogunovic D.,
RA Quintana-Murci L., Carroll T., Ma C.S., Abel L., Bousfiha A.,
RA Di Santo J.P., Glimcher L.H., Gros P., Tangye S.G., Sallusto F.,
RA Bustamante J., Casanova J.L.;
RT "Human T-bet Governs Innate and Innate-like Adaptive IFN-gamma Immunity
RT against Mycobacteria.";
RL Cell 183:1826-1847(2020).
CC -!- FUNCTION: Lineage-defining transcription factor which initiates Th1
CC lineage development from naive Th precursor cells both by activating
CC Th1 genetic programs and by repressing the opposing Th2 and Th17
CC genetic programs (PubMed:10761931). Activates transcription of a set of
CC genes important for Th1 cell function, including those encoding IFN-
CC gamma and the chemokine receptor CXCR3. Induces permissive chromatin
CC accessibilty and CpG methylation in IFNG (PubMed:33296702). Activates
CC IFNG and CXCR3 genes in part by recruiting chromatin remodeling
CC complexes including KDM6B, a SMARCA4-containing SWI/SNF-complex, and an
CC H3K4me2-methyltransferase complex to their promoters and all of these
CC complexes serve to establish a more permissive chromatin state
CC conducive with transcriptional activation (By similarity). Can activate
CC Th1 genes also via recruitment of Mediator complex and P-TEFb (composed
CC of CDK9 and CCNT1/cyclin-T1) in the form of the super elongation
CC complex (SEC) to super-enhancers and associated genes in activated Th1
CC cells (PubMed:27292648). Inhibits the Th17 cell lineage commitment by
CC blocking RUNX1-mediated transactivation of Th17 cell-specific
CC transcriptinal regulator RORC. Inhibits the Th2 cell lineage commitment
CC by suppressing the production of Th2 cytokines, such as IL-4, IL-5, and
CC IL- 13, via repression of transcriptional regulators GATA3 and NFATC2.
CC Protects Th1 cells from amplifying aberrant type-I IFN response in an
CC IFN-gamma abundant microenvironment by acting as a repressor of type-I
CC IFN transcription factors and type-I IFN-stimulated genes. Acts as a
CC regulator of antiviral B-cell responses; controls chronic viral
CC infection by promoting the antiviral antibody IgG2a isotype switching
CC and via regulation of a broad antiviral gene expression program (By
CC similarity). Required for the correct development of natural killer
CC (NK) and mucosal-associated invariant T (MAIT) cells (PubMed:33296702).
CC {ECO:0000250|UniProtKB:Q9JKD8, ECO:0000269|PubMed:10761931,
CC ECO:0000269|PubMed:27292648, ECO:0000269|PubMed:33296702}.
CC -!- SUBUNIT: Interacts with RUNX1, RUNX3, ITK, ABL1, RELA, CDK9 and KDM6B.
CC The phosphorylated form (at Thr-303) interacts with NFATC2. Interacts
CC with SMARCA4 in a KDM6B-dependent manner (By similarity). Interacts
CC with CCTN1 (PubMed:27292648). Interacts with USP10 (PubMed:24845384).
CC The phosphorylated form (at Tyr-530) interacts with GATA3
CC (PubMed:15662016). {ECO:0000250|UniProtKB:Q9JKD8,
CC ECO:0000269|PubMed:15662016, ECO:0000269|PubMed:24845384,
CC ECO:0000269|PubMed:27292648}.
CC -!- INTERACTION:
CC Q9UL17; Q92793: CREBBP; NbExp=4; IntAct=EBI-3922312, EBI-81215;
CC Q9UL17; Q09472: EP300; NbExp=5; IntAct=EBI-3922312, EBI-447295;
CC Q9UL17; P23771: GATA3; NbExp=6; IntAct=EBI-3922312, EBI-6664760;
CC Q9UL17; P08047: SP1; NbExp=4; IntAct=EBI-3922312, EBI-298336;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:24845384,
CC ECO:0000269|PubMed:33296702}.
CC -!- TISSUE SPECIFICITY: T-cell specific. {ECO:0000269|PubMed:10761931}.
CC -!- PTM: Phosphorylations at Ser-53, Tyr-77, Ser-225 and Ser-513 are
CC regulated by mTORC1. Phosphorylation at Tyr-530 is essential for its
CC interaction GATA3. Phosphorylation at Tyr-220, Tyr-266 and Tyr-305
CC enhances its transcriptional activator activity. Phosphorylation at
CC Thr-303 is required for its interaction with NFATC2.
CC {ECO:0000250|UniProtKB:Q9JKD8}.
CC -!- PTM: Ubiquitinated at Lys-314, leading to its degradation by the
CC proteasome. Ubiquitination is essential for controlling protein
CC stability, binding to the T-box-binding element of the IFN-gamma
CC promoter, and for interaction with NFATC2 through induction of
CC phosphorylation at Thr-303 (By similarity). Deubiquitinated by USP10
CC leading to its stabilization (PubMed:24845384).
CC {ECO:0000250|UniProtKB:Q9JKD8, ECO:0000269|PubMed:24845384}.
CC -!- DISEASE: Asthma, with nasal polyps and aspirin intolerance (ANPAI)
CC [MIM:208550]: A condition consisting of asthma, aspirin sensitivity and
CC nasal polyposis. Nasal polyposis is due to chronic inflammation of the
CC paranasal sinus mucosa, leading to protrusion of edematous polyps into
CC the nasal cavities. {ECO:0000269|PubMed:15806396}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC represented in this entry.
CC -!- DISEASE: Immunodeficiency 88 (IMD88) [MIM:619630]: An autosomal
CC recessive disorder characterized by the development of disseminated
CC mycobacterial disease following vaccination with BCG. Clinical features
CC included fever, lymphadenopathy, and cutaneous eruption.
CC {ECO:0000269|PubMed:33296702}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
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DR EMBL; AF093098; AAF00055.1; -; mRNA.
DR EMBL; AF241243; AAF61243.1; -; mRNA.
DR EMBL; BC039739; AAH39739.1; -; mRNA.
DR CCDS; CCDS11514.1; -.
DR RefSeq; NP_037483.1; NM_013351.1.
DR AlphaFoldDB; Q9UL17; -.
DR SMR; Q9UL17; -.
DR BioGRID; 119027; 9.
DR DIP; DIP-61303N; -.
DR IntAct; Q9UL17; 7.
DR STRING; 9606.ENSP00000177694; -.
DR iPTMnet; Q9UL17; -.
DR PhosphoSitePlus; Q9UL17; -.
DR BioMuta; TBX21; -.
DR DMDM; 12230772; -.
DR jPOST; Q9UL17; -.
DR MassIVE; Q9UL17; -.
DR MaxQB; Q9UL17; -.
DR PaxDb; Q9UL17; -.
DR PeptideAtlas; Q9UL17; -.
DR PRIDE; Q9UL17; -.
DR ProteomicsDB; 84930; -.
DR Antibodypedia; 4021; 690 antibodies from 44 providers.
DR DNASU; 30009; -.
DR Ensembl; ENST00000177694.2; ENSP00000177694.1; ENSG00000073861.3.
DR GeneID; 30009; -.
DR KEGG; hsa:30009; -.
DR MANE-Select; ENST00000177694.2; ENSP00000177694.1; NM_013351.2; NP_037483.1.
DR UCSC; uc002ilv.1; human.
DR CTD; 30009; -.
DR DisGeNET; 30009; -.
DR GeneCards; TBX21; -.
DR HGNC; HGNC:11599; TBX21.
DR HPA; ENSG00000073861; Group enriched (bone marrow, lung, lymphoid tissue).
DR MalaCards; TBX21; -.
DR MIM; 208550; phenotype.
DR MIM; 604895; gene.
DR MIM; 619630; phenotype.
DR neXtProt; NX_Q9UL17; -.
DR OpenTargets; ENSG00000073861; -.
DR PharmGKB; PA36362; -.
DR VEuPathDB; HostDB:ENSG00000073861; -.
DR eggNOG; KOG3585; Eukaryota.
DR GeneTree; ENSGT00940000160397; -.
DR HOGENOM; CLU_014430_8_2_1; -.
DR InParanoid; Q9UL17; -.
DR OMA; PGAGWPM; -.
DR OrthoDB; 374561at2759; -.
DR PhylomeDB; Q9UL17; -.
DR TreeFam; TF106341; -.
DR PathwayCommons; Q9UL17; -.
DR SignaLink; Q9UL17; -.
DR SIGNOR; Q9UL17; -.
DR BioGRID-ORCS; 30009; 34 hits in 1091 CRISPR screens.
DR GeneWiki; TBX21; -.
DR GenomeRNAi; 30009; -.
DR Pharos; Q9UL17; Tbio.
DR PRO; PR:Q9UL17; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q9UL17; protein.
DR Bgee; ENSG00000073861; Expressed in granulocyte and 110 other tissues.
DR Genevisible; Q9UL17; HS.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IEA:Ensembl.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR GO; GO:0001708; P:cell fate specification; IBA:GO_Central.
DR GO; GO:0071310; P:cellular response to organic substance; IEA:Ensembl.
DR GO; GO:0072676; P:lymphocyte migration; IDA:UniProtKB.
DR GO; GO:0032703; P:negative regulation of interleukin-2 production; ISS:UniProtKB.
DR GO; GO:2000320; P:negative regulation of T-helper 17 cell differentiation; ISS:UniProtKB.
DR GO; GO:2000329; P:negative regulation of T-helper 17 cell lineage commitment; ISS:UniProtKB.
DR GO; GO:2000552; P:negative regulation of T-helper 2 cell cytokine production; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0048304; P:positive regulation of isotype switching to IgG isotypes; IEA:Ensembl.
DR GO; GO:2000556; P:positive regulation of T-helper 1 cell cytokine production; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0045580; P:regulation of T cell differentiation; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0002296; P:T-helper 1 cell lineage commitment; ISS:UniProtKB.
DR CDD; cd00182; TBOX; 1.
DR Gene3D; 2.60.40.820; -; 1.
DR InterPro; IPR008967; p53-like_TF_DNA-bd.
DR InterPro; IPR046360; T-box_DNA-bd.
DR InterPro; IPR036960; T-box_sf.
DR InterPro; IPR001699; TF_T-box.
DR InterPro; IPR018186; TF_T-box_CS.
DR PANTHER; PTHR11267; PTHR11267; 1.
DR Pfam; PF00907; T-box; 1.
DR PRINTS; PR00937; TBOX.
DR SMART; SM00425; TBOX; 1.
DR SUPFAM; SSF49417; SSF49417; 1.
DR PROSITE; PS01283; TBOX_1; 1.
DR PROSITE; PS01264; TBOX_2; 1.
DR PROSITE; PS50252; TBOX_3; 1.
PE 1: Evidence at protein level;
KW Activator; Asthma; Disease variant; DNA-binding; Isopeptide bond; Nucleus;
KW Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..535
FT /note="T-box transcription factor TBX21"
FT /id="PRO_0000184453"
FT DNA_BIND 141..326
FT /note="T-box"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00201"
FT REGION 1..62
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 83..109
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 449..535
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 305
FT /note="Essential for its interaction with RUNX1 and its
FT ability to inhibit RUNX1 transcriptional activity and
FT suppress TH17 lineage development"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 53
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 77
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 118
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 220
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 225
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 266
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 303
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 305
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 513
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT MOD_RES 530
FT /note="Phosphotyrosine; by ITK"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT CROSSLNK 314
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q9JKD8"
FT VARIANT 33
FT /note="H -> Q (in dbSNP:rs2240017)"
FT /evidence="ECO:0000269|PubMed:15806396"
FT /id="VAR_020252"
FT VARIANT 156..157
FT /note="EM -> SL (in IMD88; loss of binding to DNA; loss of
FT transcriptional activity shown in IFNG promoter-driven
FT luciferase assay; unable to activate IFNG production)"
FT /evidence="ECO:0000269|PubMed:33296702"
FT /id="VAR_086466"
FT VARIANT 339
FT /note="I -> V (in dbSNP:rs12721471)"
FT /id="VAR_029275"
SQ SEQUENCE 535 AA; 58328 MW; 51F351335598CEF2 CRC64;
MGIVEPGCGD MLTGTEPMPG SDEGRAPGAD PQHRYFYPEP GAQDADERRG GGSLGSPYPG
GALVPAPPSR FLGAYAYPPR PQAAGFPGAG ESFPPPADAE GYQPGEGYAA PDPRAGLYPG
PREDYALPAG LEVSGKLRVA LNNHLLWSKF NQHQTEMIIT KQGRRMFPFL SFTVAGLEPT
SHYRMFVDVV LVDQHHWRYQ SGKWVQCGKA EGSMPGNRLY VHPDSPNTGA HWMRQEVSFG
KLKLTNNKGA SNNVTQMIVL QSLHKYQPRL HIVEVNDGEP EAACNASNTH IFTFQETQFI
AVTAYQNAEI TQLKIDNNPF AKGFRENFES MYTSVDTSIP SPPGPNCQFL GGDHYSPLLP
NQYPVPSRFY PDLPGQAKDV VPQAYWLGAP RDHSYEAEFR AVSMKPAFLP SAPGPTMSYY
RGQEVLAPGA GWPVAPQYPP KMGPASWFRP MRTLPMEPGP GGSEGRGPED QGPPLVWTEI
APIRPESSDS GLGEGDSKRR RVSPYPSSGD SSSPAGAPSP FDKEAEGQFY NYFPN
