Figure 2.

Regulation of cellular lysosomal homeostasis by transcription factor EB (TFEB). In homeostatic conditions, late endosomes (LE) containing lysosomal associated membrane proteins (Lamps) and Rab7 fuse with lysosomes. Multiple kinases including mTORC1, AKT, ERK2, GSKβ phosphorylate TFEB, retaining it on the lysosomal surface or sequestered to 14-3-3 chaperons in the cytoplasm. In conditions of lysosomal induction such as starvation, mTORC1 is inactivated and ROS activated MCOLN1 channel releases Ca²⁺ from lysosomal lumen to cytoplasm. The release of lysosomal Ca²⁺ locally activates calcineurin, which dephosphorylates TFEB. Protein phosphatase 2A (PP2A) is another reported TFEB phosphatase. Dephosphorylated TFEB translocates to the nucleus where it induces transcription of genes containing CLEAR elements, that include several lysosomal genes, eventually resulting in enhanced lysosomal biogenesis.