| IED ID | IndEnz0002013511 |
| Enzyme Type ID | protease013511 |
| Protein Name |
Transcription factor EB Class E basic helix-loop-helix protein 35 bHLHe35 |
| Gene Name | TFEB BHLHE35 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MASRIGLRMQLMREQAQQEEQRERMQQQAVMHYMQQQQQQQQQQLGGPPTPAINTPVHFQSPPPVPGEVLKVQSYLENPTSYHLQQSQHQKVREYLSETYGNKFAAHISPAQGSPKPPPAASPGVRAGHVLSSSAGNSAPNSPMAMLHIGSNPERELDDVIDNIMRLDDVLGYINPEMQMPNTLPLSSSHLNVYSSDPQVTASLVGVTSSSCPADLTQKRELTDAESRALAKERQKKDNHNLIERRRRFNINDRIKELGMLIPKANDLDVRWNKGTILKASVDYIRRMQKDLQKSRELENHSRRLEMTNKQLWLRIQELEMQARVHGLPTTSPSGMNMAELAQQVVKQELPSEEGPGEALMLGAEVPDPEPLPALPPQAPLPLPTQPPSPFHHLDFSHSLSFGGREDEGPPGYPEPLAPGHGSPFPSLSKKDLDLMLLDDSLLPLASDPLLSTMSPEASKASSRRSSFSMEEGDVL |
| Enzyme Length | 476 |
| Uniprot Accession Number | P19484 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:30120233, PubMed:31672913). Specifically recognizes and binds E-box sequences (5'-CANNTG-3'); efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF (PubMed:1748288, PubMed:19556463, PubMed:29146937). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, TFEB phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423). Upon starvation or lysosomal stress, inhibition of MTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423). Specifically recognizes and binds the CLEAR-box sequence (5'-GTCACGTGAC-3') present in the regulatory region of many lysosomal genes, leading to activate their expression, thereby playing a central role in expression of lysosomal genes (PubMed:19556463, PubMed:22692423). Regulates lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1 (PubMed:29146937). Acts as a positive regulator of autophagy by promoting expression of genes involved in autophagy (PubMed:21617040, PubMed:22576015, PubMed:23434374, PubMed:27278822). In association with TFE3, activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4(+) T-cells and thymus-dependent humoral immunity (By similarity). Specifically recognizes the gamma-E3 box, a subset of E-boxes, present in the heavy-chain immunoglobulin enhancer (PubMed:2115126). Plays a role in the signal transduction processes required for normal vascularization of the placenta (By similarity). Involved in the immune response to infection by the bacteria S.aureus or S.enterica, acting downstream of protein kinase D (PKD), probably by regulating cytokine and chemokine expression (By similarity). {ECO:0000250|UniProtKB:Q9R210, ECO:0000269|PubMed:1748288, ECO:0000269|PubMed:19556463, ECO:0000269|PubMed:2115126, ECO:0000269|PubMed:21617040, ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:22692423, ECO:0000269|PubMed:23434374, ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:29146937, ECO:0000269|PubMed:30120233, ECO:0000269|PubMed:31672913}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Alternative sequence (1); Chain (1); Compositional bias (3); Domain (1); Erroneous initiation (2); Modified residue (13); Motif (1); Mutagenesis (11); Region (6); Sequence conflict (3); Site (1) |
| Keywords | Activator;Adaptive immunity;Alternative splicing;Autophagy;Cytoplasm;DNA-binding;Immunity;Lysosome;Membrane;Nucleus;Phosphoprotein;Reference proteome;Transcription;Transcription regulation;Ubl conjugation |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:21617040, ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:23434374, ECO:0000269|PubMed:27184844, ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:30120233, ECO:0000269|PubMed:33691586}. Lysosome membrane {ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:22692423}. Nucleus {ECO:0000269|PubMed:21617040, ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:22692423, ECO:0000269|PubMed:23434374, ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:27184844, ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:30120233, ECO:0000269|PubMed:33691586}. Note=Mainly present in the cytoplasm (PubMed:23434374, PubMed:33691586). Under aberrant lysosomal storage conditions, it translocates from the cytoplasm to the nucleus (PubMed:21617040, PubMed:22576015, PubMed:23434374). The translocation to the nucleus is regulated by ATP13A2 (PubMed:23434374, PubMed:27278822). Colocalizes with mTORC1 on the lysosomal membrane: when nutrients are present, phosphorylation by MTOR prevents nuclear translocation and activity (PubMed:22343943, PubMed:22692423). Conversely, inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation and translocation to the nucleus (PubMed:22343943, PubMed:22692423). Exported from the nucleus in response to nutrient availability (PubMed:30120233). In macrophages, translocates into the nucleus upon live S.enterica infection (PubMed:27184844). {ECO:0000269|PubMed:21617040, ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:22692423, ECO:0000269|PubMed:23434374, ECO:0000269|PubMed:27184844, ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:30120233, ECO:0000269|PubMed:33691586}.; SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:33691586}. Note=(Microbial infection) Following Coxsackievirus B3 infection, full length TFEB and viral protease 3C-mediated cleavage product are translocated from the cytoplasm to the nucleus. {ECO:0000269|PubMed:33691586}. |
| Modified Residue | MOD_RES 109; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q9R210"; MOD_RES 114; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q9R210"; MOD_RES 122; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"; MOD_RES 138; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:30120233, ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231"; MOD_RES 142; /note="Phosphoserine; by MTOR"; /evidence="ECO:0000269|PubMed:21617040, ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:30120233, ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231"; MOD_RES 183; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:20068231"; MOD_RES 211; /note="Phosphoserine; by MTOR"; /evidence="ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:22692423, ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:30120233"; MOD_RES 332; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21617040"; MOD_RES 423; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:21617040, ECO:0007744|PubMed:23186163"; MOD_RES 441; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:20068231"; MOD_RES 466; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q9R210"; MOD_RES 467; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163"; MOD_RES 469; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q9R210" |
| Post Translational Modification | PTM: Phosphorylation by MTOR regulates its subcellular location and activity (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:24081491, PubMed:30120233). When nutrients are present, phosphorylation by MTOR promotes association with 14-3-3/YWHA adapters and retention in the cytosol (PubMed:22576015, PubMed:22343943, PubMed:22692423). Inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation and translocation to the nucleus (PubMed:22576015, PubMed:22343943, PubMed:22692423). Exported from the nucleus in a mTORC1-dependent manner in response to nutrient availability (PubMed:30120233). Dephosphorylated by phosphatase PPP3CA following Coxsackievirus B3 infection, leading to nuclear translocation (PubMed:33691586). {ECO:0000269|PubMed:21617040, ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:22692423, ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:30120233, ECO:0000269|PubMed:33691586}.; PTM: Sumoylated; does not affect dimerization with MITF. {ECO:0000269|PubMed:15507434}.; PTM: (Microbial infection) Cleavage by Coxsackievirus B3 protease 3C after site Gln-60. This non-phosphorylated cleavage product retains its ability to interact with TFEB, TFE3 or MITF and presents impaired transcriptional activity, resulting in disruption of lysosomal functions and increased viral infection. {ECO:0000269|PubMed:33691586}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 12719541; 15644781; 17285572; 19396149; 20711500; 21752829; 21804531; 21889421; 22101272; 22446944; 22786682; 23381957; 23393155; 23401004; 23602568; 24055709; 24558044; 25048860; 25108912; 25438924; 25544758; 25720963; 25790376; 25908842; 26137861; 26240184; 26264650; 26307679; 26338325; 26496610; 26596266; 26813791; 26994576; 27171064; 27172265; 27175909; 27195074; 27209302; 27252382; 27257626; 27268034; 27299292; 27373683; 27565001; 27593892; 27864122; 27892768; 28009604; 28017540; 28055300; 28102838; 28143903; 28165011; 28292013; 28656016; 28754656; 28798237; 29307831; 29316035; 29328409; 29364516; 29507340; 29689560; 29768192; 29852219; 29940807; 29992949; 30013069; 30059277; 30142454; 30145926; 30154423; 30546014; 30674024; 30677488; 30679718; 30816805; 30892133; 30979895; 31036939; 31100306; 31112550; 31119852; 31160892; 31387632; 31413743; 31448838; 31519738; 31586112; 31600176; 31609086; 31609760; 31672943; 31694921; 31717697; 31733992; 31744366; 31764220; 31820786; 31987928; 32019403; 32037305; 32098449; 32208437; 32354235; 32397616; 32408680; 32487570; 32597296; 32608399; 32622269; 32662822; 32667742; 32681035; 32716134; 32764647; 32830550; 32881934; 33163944; 33208882; 33252196; 33290695; 33297755; 33300868; 33314217; 33318473; 33416091; 33417226; 33420039; 33629334; 33851776; 33931930; 33984335; 34343492; 34356609; 34405859; 34517007; |
| Motif | MOTIF 136..153; /note=Nuclear export signal; /evidence=ECO:0000269|PubMed:30120233 |
| Gene Encoded By | |
| Mass | 52,865 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |