Protein: Transcription factor EB (Class E basic helix-loop-helix protein 35) (bHLHe35) (P19484)
Organism: Homo sapiens (Human)
Function: Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response. 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. 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. Upon starvation or lysosomal stress, inhibition of MTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity. 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. Regulates lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1. Acts as a positive regulator of autophagy by promoting expression of genes involved in autophagy. 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. 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, S.typhimurium or S.enterica: infection promotes itaconate production, leading to alkylation, resulting in nuclear localization and transcription factor activity. Itaconate-mediated alkylation activates TFEB-dependent lysosomal biogenesis, facilitating the bacteria clearance during the antibacterial innate immune response.
Subcellular location: Nucleus {ECO:0000269|PubMed:21617040, ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:22692423, ECO:0000269|PubMed:23401004, ECO:0000269|PubMed:23434374, ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:25720963, ECO:0000269|PubMed:27184844, ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:28552616, ECO:0000269|PubMed:30120233, ECO:0000269|PubMed:32612235, ECO:0000269|PubMed:32753672, ECO:0000269|PubMed:33691586, ECO:0000269|PubMed:35662396, ECO:0000269|PubMed:36697823, ECO:0000269|PubMed:37079666}. Cytoplasm, cytosol {ECO:0000269|PubMed:21617040, ECO:0000269|PubMed:22576015, ECO:0000269|PubMed:23401004, ECO:0000269|PubMed:23434374, ECO:0000269|PubMed:25720963, ECO:0000269|PubMed:27184844, ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:30120233, ECO:0000269|PubMed:32753672, ECO:0000269|PubMed:33691586, ECO:0000269|PubMed:35662396, ECO:0000269|PubMed:36697823, ECO:0000269|PubMed:37079666}. Lysosome membrane {ECO:0000269|PubMed:22343943, ECO:0000269|PubMed:22692423, ECO:0000269|PubMed:23401004, ECO:0000269|PubMed:32612235, ECO:0000269|PubMed:36697823, ECO:0000269|PubMed:37057673}. Note=Mainly present in the cytoplasm (PubMed:23434374, PubMed:33691586, PubMed:35662396). When nutrients are present, recruited to the lysosomal membrane via association with GDP-bound RagC/RRAGC (or RagD/RRAGD): it is then phosphorylated by MTOR (PubMed:23401004, PubMed:32612235, PubMed:36697823). Phosphorylation by MTOR prevents nuclear translocation and activity by promoting interaction with 14-3-3 proteins, such as YWHAZ (PubMed:22343943, PubMed:22692423, PubMed:23401004, PubMed:25720963, PubMed:32612235, PubMed:32753672, PubMed:35662396, PubMed:36697823, PubMed:37079666). Under aberrant lysosomal storage conditions, it translocates from the cytoplasm to the nucleus (PubMed:21617040, PubMed:22576015, PubMed:23434374, PubMed:25720963, PubMed:32753672). The translocation to the nucleus is regulated by ATP13A2 (PubMed:23434374, PubMed:27278822). Conversely, inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation and translocation to the nucleus (PubMed:22343943, PubMed:22692423, PubMed:37079666). 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:23401004, ECO:0000269|PubMed:23434374, ECO:0000269|PubMed:25720963, ECO:0000269|PubMed:27184844, ECO:0000269|PubMed:27278822, ECO:0000269|PubMed:30120233, ECO:0000269|PubMed:32612235, ECO:0000269|PubMed:32753672, ECO:0000269|PubMed:33691586, ECO:0000269|PubMed:35662396, ECO:0000269|PubMed:36697823, ECO:0000269|PubMed:37079666}.; 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}.
Interaction partners:
- Serine/threonine-protein kinase mTOR
- Transcription factor E3
- Microphthalmia-associated transcription factor
- Ras-related GTP-binding protein C
- Ras-related GTP-binding protein A
- Regulatory-associated protein of mTOR
- 14-3-3 protein gamma
- Target of rapamycin complex subunit LST8
- Ragulator complex protein LAMTOR1
- Ragulator complex protein LAMTOR2
Sequence:
MASRIGLRMQLMREQAQQEEQRERMQQQAVMHYMQQQQQQQQQQLGGPPTPAINTPVHFQSPPPVPGEVLKVQSYLENPTSYHLQQSQHQKVREYLSETYGNKFAAHISPAQGSPKPPPAASPGVRAGHVLSSSAGNSAPNSPMAMLHIGSNPERELDDVIDNIMRLDDVLGYINPEMQMPNTLPLSSSHLNVYSSDPQVTASLVGVTSSSCPADLTQKRELTDAESRALAKERQKKDNHNLIERRRRFNINDRIKELGMLIPKANDLDVRWNKGTILKASVDYIRRMQKDLQKSRELENHSRRLEMTNKQLWLRIQELEMQARVHGLPTTSPSGMNMAELAQQVVKQELPSEEGPGEALMLGAEVPDPEPLPALPPQAPLPLPTQPPSPFHHLDFSHSLSFGGREDEGPPGYPEPLAPGHGSPFPSLSKKDLDLMLLDDSLLPLASDPLLSTMSPEASKASSRRSSFSMEEGDVL