TFEB is a master gene for lysosomalbiogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. Under aberrant lysosomal storage conditions such as in lysosomal storage diseases, TFEB translocates from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression in cultured cells induces lysosomal biogenesis and increases the degradation of complex molecules, such as glycosaminoglycans and the pathogenic protein that causes Huntington disease. TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington disease.
TFEB is a target of the protein kinase AKT/PKB.AKT/PKB phosphorylates TFEB at serine 467 and inhibits TFEB nuclear translocation. Pharmacological inhibition of AKT/PKB activates TFEB, promotes lysosome biogenesis and autophagy, and ameliorates neuropathology in a mouse model of Juvenile Batten disease.
Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by mTORC1 and extracellular signal–regulated kinase 2 (ERK2). mTORC1 phosphorylation of TFEB occurs at the lysosomal surface, both of which are localized there by interaction with the Rag GTPases. Phosphorylated TFEB is then retained in the cytosol by interaction with 14-3-3 proteins. These kinases are tuned to the levels of extracellular nutrients suggesting a coordination in regulation of autophagy and lysomal biogenesis and partnership of two distinct cellular organelles. TFEB is activated in Trex1-deficient cells via inhibition of mTORC1 activity, resulting in an expanded lysosomal compartment.
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