Figure 4. Cellular effects of TFEB that might be of therapeutic benefit in lysosomal storage disorders.

Lysosomal Ca²⁺ efflux through TRPML1 activates the Ca²⁺-dependent phosphatase calcineurin, which mediates dephosphorylation-dependent nuclear translocation of TFEB. Nuclear TFEB up-regulates the transcription of genes involved in lysosome biogenesis and autophagy, thereby enhancing autophagic flux. In addition, Ca²⁺ efflux from peripheral lysosomes promotes lysosomal exocytosis and the secretion of non-degraded materials.