TOX_HUMAN
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 03-AUG-2022, entry version 151.
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 GlyGen; O94900; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O94900; -.
DR PhosphoSitePlus; O94900; -.
DR BioMuta; TOX; -.
DR EPD; O94900; -.
DR jPOST; O94900; -.
DR MassIVE; O94900; -.
DR MaxQB; O94900; -.
DR PaxDb; O94900; -.
DR PeptideAtlas; O94900; -.
DR PRIDE; O94900; -.
DR ProteomicsDB; 50531; -.
DR TopDownProteomics; O94900; -.
DR Antibodypedia; 11831; 166 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 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; PMQQSIG; -.
DR OrthoDB; 818359at2759; -.
DR PhylomeDB; O94900; -.
DR TreeFam; TF106481; -.
DR PathwayCommons; O94900; -.
DR SignaLink; O94900; -.
DR BioGRID-ORCS; 9760; 10 hits in 1085 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 158 other tissues.
DR Genevisible; O94900; HS.
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 Gene3D; 1.10.30.10; -; 1.
DR InterPro; IPR009071; HMG_box_dom.
DR InterPro; IPR036910; HMG_box_dom_sf.
DR Pfam; PF00505; HMG_box; 1.
DR SMART; SM00398; HMG; 1.
DR SUPFAM; SSF47095; SSF47095; 1.
DR PROSITE; PS50118; HMG_BOX_2; 1.
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
