The Nutrient-Responsive Transcription Factor TFE3, Promotes Autophagy, Lysosomal Biogenesis, and Clearance of Cellular Debris
By J. Martina, H. Diab, Li Lishu, Lim Jeong-a, Simona Patange, N. Raben, R. Puertollano. Science Signaling, 2014
623 citations recorded by the source corpus.
Enhancing TFE3 activity to promote expression of lysosome-associated genes may be beneficial in treating lysosomal storage disorders. Regulating Lysosomes and Autophagy When deprived of nutrients, cells inhibit anabolic processes, such as protein production, and promote catabolic processes, such as those mediated by lysosomes and autophagosomes. Disruption in lysosomal function causes lysosomal storage disorders. Martina et al. discovered that TFE3, like TFEB, another member of the MiTF/TFE (microphthalmia-associated transcription factor and transcription factor E) family, was inhibited at the lysosome under nutrient-replete conditions and translocated to the nucleus to stimulate genes involved in lysosome biogenesis and function and autophagy in response to nutrient deprivation. Data from various tissues and cell lines indicated that TFE3 and TFEB may be cell-specific mediators of lysosomal homeostasis. Overexpression of TFE3 stimulated lysosomal exocytosis and release of debris in a cellular model of a lysosomal storage disorder, thereby providing a potential therapeutic target. The discovery of a gene network regulating lysosomal biogenesis and its transcriptional regulator transcription factor EB (TFEB) revealed that cells monitor lysosomal function and respond to degradation requirements and environmental cues. We report the identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lysosomal biogenesis in ARPE-19 cells in response to starvation and lysosomal stress. We found that in nutrient-replete cells, TFE3 was recruited to lysosomes through interaction with active Rag guanosine triphosphatases (GTPases) and exhibited mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1)–dependent phosphorylation. Phosphorylated TFE3 was retained in the cytosol through its interaction with the cytosolic chaperone 14-3-3. After starvation, TFE3 rapidly translocated to the nucleus and bound to the CLEAR elements present in the promoter region of many lysosomal genes, thereby inducing lysosomal biogenesis. Depletion of endogenous TFE3 entirely abolished the response of ARPE-19 cells to starvation, suggesting that TFE3 plays a critical role in nutrient sensing and regulation of energy metabolism. Furthermore, overexpression of TFE3 triggered lysosomal exocytosis and resulted in efficient cellular clearance in a cellular model of a lysosomal storage disorder, Pompe disease, thus identifying TFE3 as a potential therapeutic target for the treatment of lysosomal disorders.
Subfields: Epidemiology, Physiology
View Paper: https://www.semanticscholar.org/paper/382b905731a95f2b260878d7ba6c437973405d6e
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Citations in the corpus
- Recent insights into the function of autophagy in cancer (2016, background): “MiT/TFE factors are subject to negative regulation via direct phosphorylation by mTORC1 (Roczniak-Ferguson et al. 2012; Settembre et al. 2012; Martina et al. 2014); that is, under nutrient-replete conditions, mTOR is activated and localized to the lysosome, where it phosphorylates and inactivates th”
- TFEB at a glance (2016, background): “In the case of TFE3, nutrient availability, mTORC1 activity, as well as its binding to Rag GTPases and to 14-3-3, also play a role in its cytosolic retention and inhibition of its activity (Martina et al., 2014).”