Transcription factor EB (TFEB) (TFEB)

Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and a member of the MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors (UniProt P19484). It orchestrates the expression of the Coordinated Lysosomal Expression and Regulation (CLEAR) gene network, which is critical for lysosomal biogenesis, autophagosome formation, and cellular clearance (Settembre et al., 2011, Nature). Under normal conditions, TFEB is phosphorylated by kinases such as mTORC1 and ERK2, which promotes its sequestration in the cytoplasm via 14-3-3 protein binding (Napolitano & Ballabio, 2016, Journal of Cell Science). Upon stress, nutrient deprivation, or lysosomal dysfunction, TFEB is dephosphorylated (often by calcineurin), allowing it to translocate to the nucleus and activate transcription (Medina et al., 2015, Nature). TFEB is a significant therapeutic target for neurodegenerative diseases like Alzheimer's and Parkinson's, as well as lysosomal storage disorders, where its activation can clear toxic protein aggregates (Decressac et al., 2013, PNAS). However, its dysregulation is also implicated in certain cancers, particularly renal cell carcinomas and melanomas, where it acts as an oncogene, suggesting that both activation and inhibition are viable therapeutic strategies depending on the disease context (Palmieri et al., 2011, EMBO Journal).

Other names

TCFEBBHLHE35Alpha-TFEBTranscription factor EB mRNABasic helix-loop-helix domain-containing protein 35

Activation of TFEB through dephosphorylation and nuclear translocation, leading to the upregulation of the CLEAR (Coordinated Lysosomal Expression and Regulation) gene network for enhanced lysosomal biogenesis and autophagic flux.