TFEB_MOUSE
ID TFEB_MOUSE Reviewed; 475 AA.
AC Q9R210;
DT 29-AUG-2001, integrated into UniProtKB/Swiss-Prot.
DT 29-AUG-2001, sequence version 2.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Transcription factor EB {ECO:0000303|PubMed:10036191};
GN Name=Tfeb {ECO:0000303|PubMed:10036191, ECO:0000312|MGI:MGI:103270};
GN Synonyms=Tcfeb;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ;
RX PubMed=10036191; DOI=10.1006/geno.1998.5588;
RA Rehli M., Den Elzen N., Cassady A.I., Ostrowski M.C., Hume D.A.;
RT "Cloning and characterization of the murine genes for bHLH-ZIP
RT transcription factors TFEC and TFEB reveal a common gene organization for
RT all MiT subfamily members.";
RL Genomics 56:111-120(1999).
RN [2]
RP FUNCTION, DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE.
RX PubMed=9806910; DOI=10.1242/dev.125.23.4607;
RA Steingrimsson E., Tessarollo L., Reid S.W., Jenkins N.A., Copeland N.G.;
RT "The bHLH-Zip transcription factor Tfeb is essential for placental
RT vascularization.";
RL Development 125:4607-4616(1998).
RN [3]
RP FUNCTION, DNA-BINDING, AND TISSUE SPECIFICITY.
RX PubMed=16936731; DOI=10.1038/ni1378;
RA Huan C., Kelly M.L., Steele R., Shapira I., Gottesman S.R.S., Roman C.A.J.;
RT "Transcription factors TFE3 and TFEB are critical for CD40 ligand
RT expression and thymus-dependent humoral immunity.";
RL Nat. Immunol. 7:1082-1091(2006).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-108; SER-113; SER-121;
RP SER-137; SER-141; SER-465; SER-466 AND SER-468, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Spleen, and
RC Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP FUNCTION.
RX PubMed=22343943; DOI=10.1038/emboj.2012.32;
RA Settembre C., Zoncu R., Medina D.L., Vetrini F., Erdin S., Erdin S.,
RA Huynh T., Ferron M., Karsenty G., Vellard M.C., Facchinetti V.,
RA Sabatini D.M., Ballabio A.;
RT "A lysosome-to-nucleus signalling mechanism senses and regulates the
RT lysosome via mTOR and TFEB.";
RL EMBO J. 31:1095-1108(2012).
RN [8] {ECO:0000305}
RP FUNCTION.
RX PubMed=24882217; DOI=10.1016/j.immuni.2014.05.002;
RA Visvikis O., Ihuegbu N., Labed S.A., Luhachack L.G., Alves A.M.,
RA Wollenberg A.C., Stuart L.M., Stormo G.D., Irazoqui J.E.;
RT "Innate host defense requires TFEB-mediated transcription of cytoprotective
RT and antimicrobial genes.";
RL Immunity 40:896-909(2014).
RN [9]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=27184844; DOI=10.1016/j.celrep.2016.04.052;
RA Najibi M., Labed S.A., Visvikis O., Irazoqui J.E.;
RT "An evolutionarily conserved PLC-PKD-TFEB pathway for host defense.";
RL Cell Rep. 15:1728-1742(2016).
RN [10]
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=27278822; DOI=10.1038/ncomms11803;
RA Bento C.F., Ashkenazi A., Jimenez-Sanchez M., Rubinsztein D.C.;
RT "The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate
RT autophagy via a common pathway.";
RL Nat. Commun. 7:11803-11803(2016).
RN [11]
RP FUNCTION.
RX PubMed=29146937; DOI=10.1038/s41467-017-01871-z;
RA Willett R., Martina J.A., Zewe J.P., Wills R., Hammond G.R.V.,
RA Puertollano R.;
RT "TFEB regulates lysosomal positioning by modulating TMEM55B expression and
RT JIP4 recruitment to lysosomes.";
RL Nat. Commun. 8:1580-1580(2017).
CC -!- FUNCTION: Transcription factor that acts as a master regulator of
CC lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid
CC catabolism, energy metabolism and immune response (PubMed:16936731,
CC PubMed:22343943, PubMed:27278822). Specifically recognizes and binds E-
CC box sequences (5'-CANNTG-3'); efficient DNA-binding requires
CC dimerization with itself or with another MiT/TFE family member such as
CC TFE3 or MITF (PubMed:16936731, PubMed:27278822). Involved in the
CC cellular response to amino acid availability by acting downstream of
CC MTOR: in the presence of nutrients, TFEB phosphorylation by MTOR
CC promotes its cytosolic retention and subsequent inactivation (By
CC similarity). Upon starvation or lysosomal stress, inhibition of MTOR
CC induces TFEB dephosphorylation, resulting in nuclear localization and
CC transcription factor activity (By similarity). Specifically recognizes
CC and binds the CLEAR-box sequence (5'-GTCACGTGAC-3') present in the
CC regulatory region of many lysosomal genes, leading to activate their
CC expression, thereby playing a central role in expression of lysosomal
CC genes (By similarity). Regulates lysosomal positioning in response to
CC nutrient deprivation by promoting the expression of PIP4P1
CC (PubMed:29146937). Acts as a positive regulator of autophagy by
CC promoting expression of genes involved in autophagy (PubMed:27278822).
CC In association with TFE3, activates the expression of CD40L in T-cells,
CC thereby playing a role in T-cell-dependent antibody responses in
CC activated CD4(+) T-cells and thymus-dependent humoral immunity
CC (PubMed:16936731). Specifically recognizes the gamma-E3 box, a subset
CC of E-boxes, present in the heavy-chain immunoglobulin enhancer (By
CC similarity). Plays a role in the signal transduction processes required
CC for normal vascularization of the placenta (PubMed:9806910). Involved
CC in the immune response to infection by the bacteria S.aureus or
CC S.enterica, acting downstream of protein kinase D (PKD), probably by
CC regulating cytokine and chemokine expression (PubMed:24882217,
CC PubMed:27184844). {ECO:0000250|UniProtKB:P19484,
CC ECO:0000269|PubMed:16936731, ECO:0000269|PubMed:22343943,
CC ECO:0000269|PubMed:24882217, ECO:0000269|PubMed:27184844,
CC ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:29146937,
CC ECO:0000269|PubMed:9806910}.
CC -!- SUBUNIT: Homodimer and heterodimer; with TFE3 or MITF.
CC {ECO:0000250|UniProtKB:P19484}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:27278822}.
CC Lysosome membrane {ECO:0000250|UniProtKB:P19484}. Nucleus
CC {ECO:0000269|PubMed:27278822}. Note=Mainly present in the cytoplasm (By
CC similarity). Under aberrant lysosomal storage conditions, it
CC translocates from the cytoplasm to the nucleus (By similarity). The
CC translocation to the nucleus is regulated by ATP13A2 (PubMed:27278822).
CC Colocalizes with mTORC1 on the lysosomal membrane: when nutrients are
CC present, phosphorylation by MTOR prevents nuclear translocation and
CC activity (By similarity). Conversely, inhibition of mTORC1, starvation
CC and lysosomal disruption, promotes dephosphorylation and translocation
CC to the nucleus (By similarity). Exported from the nucleus in response
CC to nutrient availability (By similarity). In macrophages, translocates
CC into the nucleus upon live S.enterica infection (By similarity).
CC {ECO:0000250|UniProtKB:P19484, ECO:0000269|PubMed:27278822}.
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:16936731}.
CC -!- DEVELOPMENTAL STAGE: Expressed at low levels in the embryo but at high
CC levels in the labyrinthine trophoblast cells of the placenta.
CC {ECO:0000269|PubMed:9806910}.
CC -!- DOMAIN: The leucine zipper region is essential for homo- or
CC heterodimerization and high-affinity DNA binding. DNA binding is
CC mediated by the basic region. {ECO:0000250|UniProtKB:P19484}.
CC -!- PTM: Sumoylated; does not affect dimerization with MITF.
CC {ECO:0000250|UniProtKB:P19484}.
CC -!- PTM: Phosphorylation by MTOR regulates its subcellular location and
CC activity. When nutrients are present, phosphorylation by MTOR promotes
CC association with 14-3-3/YWHA adapters and retention in the cytosol.
CC Inhibition of mTORC1, starvation and lysosomal disruption, promotes
CC dephosphorylation and translocation to the nucleus. Exported from the
CC nucleus in a mTORC1-dependent manner in response to nutrient
CC availability. {ECO:0000250|UniProtKB:P19484}.
CC -!- DISRUPTION PHENOTYPE: Death between 9.5 and 10.5 days in embryonic
CC development. Embryos display severe defects in placental
CC vascularization. The embryonic vasculature forms normally but few
CC vessels are seen entering the placenta and those that do enter fail to
CC thrive and branch normally. {ECO:0000269|PubMed:9806910}.
CC -!- SIMILARITY: Belongs to the MiT/TFE family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD20979.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF079095; AAD20979.1; ALT_INIT; mRNA.
DR CCDS; CCDS50133.1; -.
DR RefSeq; NP_001155194.1; NM_001161722.1.
DR RefSeq; NP_001155195.1; NM_001161723.1.
DR RefSeq; NP_035679.3; NM_011549.3.
DR RefSeq; XP_006524066.2; XM_006524003.3.
DR RefSeq; XP_006524069.1; XM_006524006.3.
DR RefSeq; XP_006524070.1; XM_006524007.3.
DR AlphaFoldDB; Q9R210; -.
DR SMR; Q9R210; -.
DR BioGRID; 204016; 15.
DR IntAct; Q9R210; 1.
DR STRING; 10090.ENSMUSP00000024786; -.
DR iPTMnet; Q9R210; -.
DR PhosphoSitePlus; Q9R210; -.
DR EPD; Q9R210; -.
DR jPOST; Q9R210; -.
DR MaxQB; Q9R210; -.
DR PaxDb; Q9R210; -.
DR PRIDE; Q9R210; -.
DR ProteomicsDB; 258862; -.
DR Antibodypedia; 15889; 621 antibodies from 44 providers.
DR DNASU; 21425; -.
DR Ensembl; ENSMUST00000086932; ENSMUSP00000084151; ENSMUSG00000023990.
DR Ensembl; ENSMUST00000113288; ENSMUSP00000108913; ENSMUSG00000023990.
DR GeneID; 21425; -.
DR KEGG; mmu:21425; -.
DR UCSC; uc008cwc.2; mouse.
DR CTD; 7942; -.
DR MGI; MGI:103270; Tfeb.
DR VEuPathDB; HostDB:ENSMUSG00000023990; -.
DR eggNOG; KOG1318; Eukaryota.
DR GeneTree; ENSGT00940000159691; -.
DR HOGENOM; CLU_031638_3_1_1; -.
DR InParanoid; Q9R210; -.
DR OrthoDB; 1211990at2759; -.
DR PhylomeDB; Q9R210; -.
DR BioGRID-ORCS; 21425; 5 hits in 74 CRISPR screens.
DR ChiTaRS; Tfeb; mouse.
DR PRO; PR:Q9R210; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; Q9R210; protein.
DR Bgee; ENSMUSG00000023990; Expressed in hindlimb stylopod muscle and 185 other tissues.
DR ExpressionAtlas; Q9R210; baseline and differential.
DR Genevisible; Q9R210; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; IDA:MGI.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; ISS:UniProtKB.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IMP:UniProtKB.
DR GO; GO:0001892; P:embryonic placenta development; IMP:UniProtKB.
DR GO; GO:0006959; P:humoral immune response; IMP:UniProtKB.
DR GO; GO:0032418; P:lysosome localization; ISO:MGI.
DR GO; GO:0007040; P:lysosome organization; IMP:MGI.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; ISO:MGI.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR InterPro; IPR021802; MiT/TFE_C.
DR InterPro; IPR031867; MiT/TFE_N.
DR InterPro; IPR024098; TFEB.
DR PANTHER; PTHR45776:SF5; PTHR45776:SF5; 1.
DR Pfam; PF11851; DUF3371; 1.
DR Pfam; PF00010; HLH; 1.
DR Pfam; PF15951; MITF_TFEB_C_3_N; 1.
DR SMART; SM00353; HLH; 1.
DR SUPFAM; SSF47459; SSF47459; 1.
DR PROSITE; PS50888; BHLH; 1.
PE 1: Evidence at protein level;
KW Activator; Adaptive immunity; Autophagy; Cytoplasm; DNA-binding; Immunity;
KW Lysosome; Membrane; Nucleus; Phosphoprotein; Reference proteome;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..475
FT /note="Transcription factor EB"
FT /id="PRO_0000127474"
FT DOMAIN 234..287
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT REGION 1..52
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 155..164
FT /note="Strong transcription activation domain"
FT /evidence="ECO:0000255"
FT REGION 297..318
FT /note="Leucine-zipper"
FT REGION 351..429
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 445..475
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 135..152
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:P19484"
FT COMPBIAS 22..49
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 368..383
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 451..468
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 108
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 113
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 121
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 137
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 141
FT /note="Phosphoserine; by MTOR"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 182
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P19484"
FT MOD_RES 210
FT /note="Phosphoserine; by MTOR"
FT /evidence="ECO:0000250|UniProtKB:P19484"
FT MOD_RES 331
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P19484"
FT MOD_RES 422
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P19484"
FT MOD_RES 440
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P19484"
FT MOD_RES 465
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 466
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 468
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
SQ SEQUENCE 475 AA; 52614 MW; 4249C6F501968326 CRC64;
MASRIGLRMQ LMREQAQQEE QRERMQQQAV MHYMQQQQQQ QQQLGGPPTP AINTPVHFQS
PPPVPGEVLK VQSYLENPTS YHLQQSQHQK VREYLSETYG NKFAAHVSPA QGSPKPAPAA
SPGVRAGHVL STSAGNSAPN SPMAMLHISS NPEKEFDDVI DNIMRLDSVL GYINPEMQMP
NTLPLSSSHL NVYSGDPQVT ASMVGVTSSS CPADLTQKRE LTDAESRALA KERQKKDNHN
LIERRRRFNI NDRIKELGML IPKANDLDVR WNKGTILKAS VDYIRRMQKD LQKSRELENH
SRRLEMTNKQ LWLRIQELEM QARVHGLPTT SPSGVNMAEL AQQVVKQELP SEDGPGEALM
LGPEVPEPEQ MPALPPQAPL PSAAQPQSPF HHLDFSHGLS FGGGGDEGPT GYPDTLGTEH
GSPFPNLSKK DLDLMLLDDS LLPLASDPLF STMSPEASKA SSRRSSFSME EGDVL
