ID   TOX_HUMAN               Reviewed;         526 AA.
AC   O94900; Q96AV5;
DT   27-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT   27-JUN-2006, sequence version 3.
DT   24-JAN-2024, entry version 159.
DE   RecName: Full=Thymocyte selection-associated high mobility group box protein TOX {ECO:0000303|PubMed:21126536};
DE   AltName: Full=Thymus high mobility group box protein TOX {ECO:0000303|PubMed:21126536};
GN   Name=TOX {ECO:0000303|PubMed:21126536, ECO:0000312|HGNC:HGNC:18988};
GN   Synonyms=KIAA0808;
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 [LARGE SCALE MRNA].
RC   TISSUE=Brain;
RX   PubMed=9872452; DOI=10.1093/dnares/5.5.277;
RA   Nagase T., Ishikawa K., Suyama M., Kikuno R., Miyajima N., Tanaka A.,
RA   Kotani H., Nomura N., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. XI. The
RT   complete sequences of 100 new cDNA clones from brain which code for large
RT   proteins in vitro.";
RL   DNA Res. 5:277-286(1998).
RN   [2]
RP   SEQUENCE REVISION.
RX   PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA   Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT   "Construction of expression-ready cDNA clones for KIAA genes: manual
RT   curation of 330 KIAA cDNA clones.";
RL   DNA Res. 9:99-106(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lymph;
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   VARIANT THR-267.
RX   PubMed=21248752; DOI=10.1038/nature09639;
RA   Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H.,
RA   Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J.,
RA   Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M.,
RA   Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L.,
RA   Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J.,
RA   Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A.,
RA   Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K.,
RA   Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.;
RT   "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene
RT   PBRM1 in renal carcinoma.";
RL   Nature 469:539-542(2011).
RN   [5]
RP   FUNCTION, INDUCTION, AND TISSUE SPECIFICITY.
RX   PubMed=21126536; DOI=10.1016/j.imlet.2010.11.008;
RA   Yun S., Lee S.H., Yoon S.R., Kim M.S., Piao Z.H., Myung P.K., Kim T.D.,
RA   Jung H., Choi I.;
RT   "TOX regulates the differentiation of human natural killer cells from
RT   hematopoietic stem cells in vitro.";
RL   Immunol. Lett. 136:29-36(2011).
RN   [6]
RP   TISSUE SPECIFICITY.
RX   PubMed=31207604; DOI=10.1038/s41586-019-1324-y;
RA   Scott A.C., Duendar F., Zumbo P., Chandran S.S., Klebanoff C.A.,
RA   Shakiba M., Trivedi P., Menocal L., Appleby H., Camara S., Zamarin D.,
RA   Walther T., Snyder A., Femia M.R., Comen E.A., Wen H.Y., Hellmann M.D.,
RA   Anandasabapathy N., Liu Y., Altorki N.K., Lauer P., Levy O., Glickman M.S.,
RA   Kaye J., Betel D., Philip M., Schietinger A.;
RT   "TOX is a critical regulator of tumour-specific T cell differentiation.";
RL   Nature 571:270-274(2019).
CC   -!- FUNCTION: Transcriptional regulator with a major role in neural stem
CC       cell commitment and corticogenesis as well as in lymphoid cell
CC       development and lymphoid tissue organogenesis (By similarity). Binds to
CC       GC-rich DNA sequences in the proximity of transcription start sites and
CC       may alter chromatin structure, modifying access of transcription
CC       factors to DNA. During cortical development, controls the neural stem
CC       cell pool by inhibiting the switch from proliferative to
CC       differentiating progenitors. Beyond progenitor cells, promotes neurite
CC       outgrowth in newborn neurons migrating to reach the cortical plate. May
CC       activate or repress critical genes for neural stem cell fate such as
CC       SOX2, EOMES and ROBO2 (By similarity). Plays an essential role in the
CC       development of lymphoid tissue-inducer (LTi) cells, a subset necessary
CC       for the formation of secondary lymphoid organs: peripheral lymph nodes
CC       and Peyer's patches. Acts as a developmental checkpoint and regulates
CC       thymocyte positive selection toward T cell lineage commitment. Required
CC       for the development of various T cell subsets, including CD4-positive
CC       helper T cells, CD8-positive cytotoxic T cells, regulatory T cells and
CC       CD1D-dependent natural killer T (NKT) cells. Required for the
CC       differentiation of common lymphoid progenitors (CMP) to innate lymphoid
CC       cells (ILC) (By similarity). May regulate the NOTCH-mediated gene
CC       program, promoting differentiation of the ILC lineage. Required at the
CC       progenitor phase of NK cell development in the bone marrow to specify
CC       NK cell lineage commitment (PubMed:21126536) (By similarity). Upon
CC       chronic antigen stimulation, diverts T cell development by promoting
CC       the generation of exhaustive T cells, while suppressing effector and
CC       memory T cell programming. May regulate the expression of genes
CC       encoding inhibitory receptors such as PDCD1 and induce the exhaustion
CC       program, to prevent the overstimulation of T cells and activation-
CC       induced cell death (By similarity). {ECO:0000250|UniProtKB:Q66JW3,
CC       ECO:0000269|PubMed:21126536}.
CC   -!- SUBUNIT: Interacts with HBO1 complex composed at least of KAT7/HBO1,
CC       ING4, MEAF6, and JADE2; this complex is involved in histone
CC       acetylation. Interacts with DNMT1, LEO1, PAF1, SAP130 and SIN3A; these
CC       interactors regulate chromatin remodeling. Interacts with an array of
CC       proteins involved in RNA processing and translation and DNA
CC       replication. {ECO:0000250|UniProtKB:Q66JW3}.
CC   -!- INTERACTION:
CC       O94900; Q8N9N5-2: BANP; NbExp=3; IntAct=EBI-9088321, EBI-11524452;
CC       O94900; Q96MA1: DMRTB1; NbExp=3; IntAct=EBI-9088321, EBI-954466;
CC       O94900; Q13588: GRAP; NbExp=3; IntAct=EBI-9088321, EBI-2847510;
CC       O94900; Q92876: KLK6; NbExp=3; IntAct=EBI-9088321, EBI-2432309;
CC       O94900; P59990: KRTAP12-1; NbExp=3; IntAct=EBI-9088321, EBI-10210845;
CC       O94900; Q6PEX3: KRTAP26-1; NbExp=3; IntAct=EBI-9088321, EBI-3957672;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00267}.
CC   -!- TISSUE SPECIFICITY: Expressed in NK cells (PubMed:21126536). Highly
CC       expressed in tumor-infiltrating CD8-positive T cells (at protein level)
CC       (PubMed:31207604). {ECO:0000269|PubMed:21126536,
CC       ECO:0000269|PubMed:31207604}.
CC   -!- INDUCTION: Up-regulated during differentiation of NK cells from CD34-
CC       positive hematopoietic cells in the presence of IL15. Down-regulated in
CC       mature NK cells. {ECO:0000269|PubMed:21126536}.
CC   -!- SIMILARITY: Belongs to the high motility group (HMG) box superfamily.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA34528.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AB018351; BAA34528.2; ALT_INIT; mRNA.
DR   EMBL; BC016665; AAH16665.1; -; mRNA.
DR   CCDS; CCDS34897.1; -.
DR   RefSeq; NP_055544.1; NM_014729.2.
DR   AlphaFoldDB; O94900; -.
DR   BMRB; O94900; -.
DR   SMR; O94900; -.
DR   BioGRID; 115107; 10.
DR   IntAct; O94900; 8.
DR   STRING; 9606.ENSP00000354842; -.
DR   BindingDB; O94900; -.
DR   GlyCosmos; O94900; 1 site, 1 glycan.
DR   GlyGen; O94900; 3 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; O94900; -.
DR   PhosphoSitePlus; O94900; -.
DR   BioMuta; TOX; -.
DR   EPD; O94900; -.
DR   jPOST; O94900; -.
DR   MassIVE; O94900; -.
DR   MaxQB; O94900; -.
DR   PaxDb; 9606-ENSP00000354842; -.
DR   PeptideAtlas; O94900; -.
DR   ProteomicsDB; 50531; -.
DR   TopDownProteomics; O94900; -.
DR   Antibodypedia; 11831; 186 antibodies from 30 providers.
DR   DNASU; 9760; -.
DR   Ensembl; ENST00000361421.2; ENSP00000354842.1; ENSG00000198846.6.
DR   GeneID; 9760; -.
DR   KEGG; hsa:9760; -.
DR   MANE-Select; ENST00000361421.2; ENSP00000354842.1; NM_014729.3; NP_055544.1.
DR   UCSC; uc003xtw.1; human.
DR   AGR; HGNC:18988; -.
DR   CTD; 9760; -.
DR   DisGeNET; 9760; -.
DR   GeneCards; TOX; -.
DR   HGNC; HGNC:18988; TOX.
DR   HPA; ENSG00000198846; Tissue enriched (lymphoid).
DR   MIM; 606863; gene.
DR   neXtProt; NX_O94900; -.
DR   OpenTargets; ENSG00000198846; -.
DR   PharmGKB; PA162406704; -.
DR   VEuPathDB; HostDB:ENSG00000198846; -.
DR   eggNOG; KOG0381; Eukaryota.
DR   GeneTree; ENSGT00940000159497; -.
DR   HOGENOM; CLU_030650_2_0_1; -.
DR   InParanoid; O94900; -.
DR   OMA; QPGMSPH; -.
DR   OrthoDB; 4252846at2759; -.
DR   PhylomeDB; O94900; -.
DR   TreeFam; TF106481; -.
DR   PathwayCommons; O94900; -.
DR   SignaLink; O94900; -.
DR   BioGRID-ORCS; 9760; 13 hits in 1169 CRISPR screens.
DR   ChiTaRS; TOX; human.
DR   GeneWiki; TOX; -.
DR   GenomeRNAi; 9760; -.
DR   Pharos; O94900; Tbio.
DR   PRO; PR:O94900; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   RNAct; O94900; Protein.
DR   Bgee; ENSG00000198846; Expressed in cortical plate and 159 other cell types or tissues.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0031490; F:chromatin DNA binding; ISS:UniProtKB.
DR   GO; GO:0043373; P:CD4-positive, alpha-beta T cell lineage commitment; ISS:UniProtKB.
DR   GO; GO:0002362; P:CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment; ISS:UniProtKB.
DR   GO; GO:0043375; P:CD8-positive, alpha-beta T cell lineage commitment; ISS:UniProtKB.
DR   GO; GO:0021895; P:cerebral cortex neuron differentiation; ISS:UniProtKB.
DR   GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR   GO; GO:0002521; P:leukocyte differentiation; IBA:GO_Central.
DR   GO; GO:0048535; P:lymph node development; IEA:Ensembl.
DR   GO; GO:0001779; P:natural killer cell differentiation; IMP:UniProtKB.
DR   GO; GO:0002364; P:NK T cell lineage commitment; ISS:UniProtKB.
DR   GO; GO:0048541; P:Peyer's patch development; IEA:Ensembl.
DR   GO; GO:1901537; P:positive regulation of DNA demethylation; ISS:UniProtKB.
DR   GO; GO:0032825; P:positive regulation of natural killer cell differentiation; IEA:Ensembl.
DR   GO; GO:2000179; P:positive regulation of neural precursor cell proliferation; ISS:UniProtKB.
DR   GO; GO:0010976; P:positive regulation of neuron projection development; ISS:UniProtKB.
DR   GO; GO:1902232; P:regulation of positive thymic T cell selection; ISS:UniProtKB.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   CDD; cd21995; HMG-box_TOX-like; 1.
DR   Gene3D; 1.10.30.10; High mobility group box domain; 1.
DR   InterPro; IPR009071; HMG_box_dom.
DR   InterPro; IPR036910; HMG_box_dom_sf.
DR   PANTHER; PTHR45781; AGAP000281-PA; 1.
DR   PANTHER; PTHR45781:SF4; THYMOCYTE SELECTION-ASSOCIATED HIGH MOBILITY GROUP BOX PROTEIN TOX; 1.
DR   Pfam; PF00505; HMG_box; 1.
DR   PRINTS; PR00886; HIGHMOBLTY12.
DR   SMART; SM00398; HMG; 1.
DR   SUPFAM; SSF47095; HMG-box; 1.
DR   PROSITE; PS50118; HMG_BOX_2; 1.
DR   Genevisible; O94900; HS.
PE   1: Evidence at protein level;
KW   Chromatin regulator; DNA-binding; Neurogenesis; Nucleus;
KW   Reference proteome; Transcription; Transcription regulation.
FT   CHAIN           1..526
FT                   /note="Thymocyte selection-associated high mobility group
FT                   box protein TOX"
FT                   /id="PRO_0000244569"
FT   DNA_BIND        261..329
FT                   /note="HMG box"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00267"
FT   REGION          138..178
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          192..264
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           237..256
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        138..154
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        192..220
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        221..246
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VARIANT         267
FT                   /note="A -> T (found in a renal cell carcinoma sample;
FT                   somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:21248752"
FT                   /id="VAR_064759"
FT   CONFLICT        9
FT                   /note="P -> V (in Ref. 3; AAH16665)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   526 AA;  57513 MW;  5AE4C5B07F2EB8FF CRC64;
     MDVRFYPPPA QPAAAPDAPC LGPSPCLDPY YCNKFDGENM YMSMTEPSQD YVPASQSYPG
     PSLESEDFNI PPITPPSLPD HSLVHLNEVE SGYHSLCHPM NHNGLLPFHP QNMDLPEITV
     SNMLGQDGTL LSNSISVMPD IRNPEGTQYS SHPQMAAMRP RGQPADIRQQ PGMMPHGQLT
     TINQSQLSAQ LGLNMGGSNV PHNSPSPPGS KSATPSPSSS VHEDEGDDTS KINGGEKRPA
     SDMGKKPKTP KKKKKKDPNE PQKPVSAYAL FFRDTQAAIK GQNPNATFGE VSKIVASMWD
     GLGEEQKQVY KKKTEAAKKE YLKQLAAYRA SLVSKSYSEP VDVKTSQPPQ LINSKPSVFH
     GPSQAHSALY LSSHYHQQPG MNPHLTAMHP SLPRNIAPKP NNQMPVTVSI ANMAVSPPPP
     LQISPPLHQH LNMQQHQPLT MQQPLGNQLP MQVQSALHSP TMQQGFTLQP DYQTIINPTS
     TAAQVVTQAM EYVRSGCRNP PPQPVDWNND YCSSGGMQRD KALYLT
//