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 . In association with ACSS2, promotes the expression of genes involved in lysosome biogenesis and both autophagy upon glucose deprivation .
Subcellular locations: Nucleus, Cytoplasm, Cytosol, Lysosome membrane
Mainly present in the cytoplasm ( ). 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 ( ). Phosphorylation by MTOR prevents nuclear translocation and activity by promoting interaction with 14-3-3 proteins, such as YWHAZ (    ). Under aberrant lysosomal storage conditions, it translocates from the cytoplasm to the nucleus (  ). The translocation to the nucleus is regulated by ATP13A2 (, ). Conversely, inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation and translocation to the nucleus ( ). Exported from the nucleus in response to nutrient availability . In macrophages, translocates into the nucleus upon live S.enterica infection .
Subcellular locations: Nucleus
(Microbial infection) Following Coxsackievirus B3 infection, full length TFEB and viral protease 3C-mediated cleavage product are translocated from the cytoplasm to the nucleus.