TFEB (Transcription factor EB)

TFEB is a basic helix-loop-helix transcription factor that acts as a master regulator of autophagy and lysosomal biogenesis. It binds a conserved promoter motif called the CLEAR (Coordinated Lysosomal Expression and Regulation) element to drive coordinated transcription of genes encoding lysosomal hydrolases, lysosomal membrane proteins and core autophagy components such as ATG genes. Under nutrient-replete conditions, mTORC1 on the lysosomal surface phosphorylates TFEB at residues including Ser211, creating a 14-3-3 binding site that retains TFEB in the cytoplasm. Starvation, lysosomal stress or pharmacological inhibition of mTORC1 lead to dephosphorylation and nuclear translocation, where TFEB induces the CLEAR network. In aging models, sustained TFEB activity enhances clearance of damaged proteins and organelles and has been linked to improved proteostasis.