TFEBmediated

TFEBmediated refers to cellular processes governed by transcription factor EB (TFEB), a member of the MiTF/TFE transcription factor family that acts as a master regulator of autophagy and lysosome biogenesis. TFEB and its related factors coordinate the expression of a broad network of genes involved in lysosome function, autophagy, and cellular clearance.

Mechanism and regulation: Under nutrient-rich conditions, TFEB is phosphorylated by mTORC1 and retained in the cytoplasm. Starvation, lysosomal stress, or calcium signaling activate phosphatases such as calcineurin, leading to TFEB dephosphorylation and translocation into the nucleus. In the nucleus, TFEB binds CLEAR elements (Coordinated Lysosomal Expression and Regulation) in target gene promoters, upregulating lysosomal hydrolases, membrane proteins, and autophagy-related genes. TFEB activity is modulated by various kinases and phosphatases, including ERK, MAPK, and GSK3, which influence its localization and transcriptional activity, and by cross-talk with the lysosome and metabolic state.

Biological roles: TFEBmediated programs enhance lysosome biogenesis and autophagic flux, promoting degradation of damaged organelles, protein aggregates, and intracellular pathogens. This regulation supports cellular adaptation to stress, modulates metabolism, and can influence immune responses. TFEB function often overlaps with that of TFE3 and MiTF, providing redundancy in certain tissues and conditions.

Clinical relevance and therapeutics: Impaired TFEB function and autophagy-lysosome insufficiency are linked to neurodegenerative diseases and lysosomal storage disorders. Conversely, activating TFEB mediates clearance of pathological aggregates and improves lysosomal capacity in experimental models. Pharmacological strategies aim to promote TFEB nuclear localization or mimic its transcriptional program, including mTOR inhibition and compounds that trigger lysosomal stress responses.

Evolution and context: TFEBmediated pathways are conserved across vertebrates, with core components of the CLEAR network preserved to regulate lysosome and autophagy-related gene expression.