Article

The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis

Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
Science Signaling (Impact Factor: 6.28). 06/2012; 5(228):ra42. DOI: 10.1126/scisignal.2002790
Source: PubMed

ABSTRACT

Lysosomes are the major cellular site for clearance of defective organelles and digestion of internalized material. Demand on lysosomal capacity can vary greatly, and lysosomal function must be adjusted to maintain cellular homeostasis. Here, we identified an interaction between the lysosome-localized mechanistic target of rapamycin complex 1 (mTORC1) and the transcription factor TFEB (transcription factor EB), which promotes lysosome biogenesis. When lysosomal activity was adequate, mTOR-dependent phosphorylation of TFEB on Ser(211) triggered the binding of 14-3-3 proteins to TFEB, resulting in retention of the transcription factor in the cytoplasm. Inhibition of lysosomal function reduced the mTOR-dependent phosphorylation of TFEB, resulting in diminished interactions between TFEB and 14-3-3 proteins and the translocation of TFEB into the nucleus, where it could stimulate genes involved in lysosomal biogenesis. These results identify TFEB as a target of mTOR and suggest a mechanism for matching the transcriptional regulation of genes encoding proteins of autophagosomes and lysosomes to cellular need. The closely related transcription factors MITF (microphthalmia transcription factor) and TFE3 (transcription factor E3) also localized to lysosomes and accumulated in the nucleus when lysosome function was inhibited, thus broadening the range of physiological contexts under which this regulatory mechanism may prove important.

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Available from: Tobias Walther, Feb 06, 2014
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    • "Interestingly, mTORC1 associates and phosphorylates TFEB at the lysosomal membrane under conditions of nutrient sufficiency and thus prevents its translocation to the nucleus. In response to cellular energy depletion, however, mTORC1- dependent phosphorylation of TFEB is impaired, triggering the transcription of genes that encode proteins required for autophagosome formation and autophagic flux (Martina et al., 2012; Roczniak-Ferguson et al., 2012). Given its central role in regulating the autophagy-lysosomal pathway , TFEB has gained significant attention as a potential therapeutic target for diseases where defective autophagy and/or lysosomal dysfunction have been implicated, such as hepatic 1-antitrypsin deficiency (Pastore et al., 2013), Pompe disease (Spampanato et al., 2013), Parkinson's disease (Decressac et al., 2013) or Huntington's disease (Tsunemi et al., 2012). "
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    • "Further work is required to determine how TFEB is activated. TFEB can be phosphorylated by kinases such as mTORC1 and protein kinase Cb (Martina et al. 2012;Roczniak-Ferguson et al. 2012;Settembre et al. 2012;Ferron et al. 2013), with phosphorylation of serines being implicated in both preventing nuclear translocation of TFEB (Martina et al. 2012;Roczniak-Ferguson et al. 2012) and being required for the biological functions of TFEB (Pe~Llopis et al. 2011;Ferron et al. 2013). Since PINK1 is a serine/threonine kinase, it is a putative candidate for directly phosphorylating TFEB or initiating a kinase cascade to activate TFEB. "
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    • "In wing discs expressing Mitf in the posterior half (en- Gal4 UAS-Mitf ) and Rab7–YFP constitutively throughout the epithelium (tub-Rab7-YFP), we observed a dramatic increase in Rab7–YFP staining in the posterior as compared to the anterior region (Fig. 3G). Interestingly, Mitf like Rab7–YFP, showed a punctate distribution typical of vesicles and in many cases the punctate signals overlapped, suggesting an association of fly Mitf with lysosomes that is reminiscent of the mammalian factors (Fig. 3G, inset) (Martina et al., 2012; Roczniak-Ferguson et al., 2012; Settembre et al., 2012). Similarly, in dpp-Gal4 UAS-spin- GFP wing discs (without exogenous Mitf ), the Spin–GFP fusion protein localized apically, as expected for mature lysosomes, in cells at the center of the dpp-Gal4 stripe (Fig. 3H, left panel). "
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