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 02-SEP-2026, entry version 191. 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 accessibility 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. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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_013351.2. DR AlphaFoldDB; Q9UL17; -. DR SMR; Q9UL17; -. DR BioGRID; 119027; 11. DR DIP; DIP-61303N; -. DR FunCoup; Q9UL17; 612. DR IntAct; Q9UL17; 7. DR NDEx; IQUERY-CP-TBX21; 7 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000177694; -. DR GlyGen; Q9UL17; 1 site. DR iPTMnet; Q9UL17; -. DR PhosphoSitePlus; Q9UL17; -. DR BioMuta; TBX21; -. DR DMDM; 12230772; -. DR jPOST; Q9UL17; -. DR MassIVE; Q9UL17; -. DR PaxDb; 9606-ENSP00000177694; -. DR PeptideAtlas; Q9UL17; -. DR ProteomicsDB; 84930; -. DR Antibodypedia; 4021; 720 antibodies from 47 providers. DR DNASU; 30009; -. DR Ensembl; ENST00000177694.2; ENSP00000177694.1; ENSG00000073861.4. 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 AGR; HGNC:11599; -. DR ClinPGx; PA36362; -. 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 OpenTargets; ENSG00000073861; -. DR VEuPathDB; HostDB:ENSG00000073861; -. DR eggNOG; KOG3585; Eukaryota. DR GeneTree; ENSGT00940000160397; -. DR HOGENOM; CLU_014430_8_2_1; -. DR InParanoid; Q9UL17; -. DR OMA; AGWPMAP; -. DR OrthoDB; 7442607at2759; -. DR PAN-GO; Q9UL17; 7 GO annotations based on evolutionary models. DR PhylomeDB; Q9UL17; -. DR PathwayCommons; Q9UL17; -. DR Reactome; R-HSA-9942503; Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells). DR SignaLink; Q9UL17; -. DR SIGNOR; Q9UL17; -. DR Agora; ENSG00000073861; -. DR BioGRID-ORCS; 30009; 41 hits in 1172 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 111 other cell types or tissues. DR GO; GO:0000785; C:chromatin; IBA:GO_Central. DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; EXP: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:0002523; P:leukocyte migration involved in inflammatory response; IEA:Ensembl. DR GO; GO:0072676; P:lymphocyte migration; IDA:UniProtKB. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISS: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:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. 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: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:0071548; P:response to dexamethasone; IEA:Ensembl. 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; cd20203; T-box_TBX21; 1. DR FunFam; 2.60.40.820:FF:000011; T-box transcription factor TBX21; 1. DR Gene3D; 2.60.40.820; Transcription factor, T-box; 1. DR InterPro; IPR008967; p53-like_TF_DNA-bd_sf. 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; T-BOX PROTEIN-RELATED; 1. DR PANTHER; PTHR11267:SF125; T-BOX TRANSCRIPTION FACTOR TBX21; 1. DR Pfam; PF00907; T-box; 1. DR PRINTS; PR00937; TBOX. DR SMART; SM00425; TBOX; 1. DR SUPFAM; SSF49417; p53-like transcription factors; 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; Proteomics identification; Reference proteome; Repressor; KW Transcription; 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 COMPBIAS 503..520 FT /note="Low complexity" 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 //