The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis
Top Cited Papers
- 12 June 2012
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 5 (228), ra42
- https://doi.org/10.1126/scisignal.2002790
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 Ser211 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.Keywords
This publication has 65 references indexed in Scilit:
- A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEBThe EMBO Journal, 2012
- Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular ClearanceDevelopmental Cell, 2011
- Regulation of TFEB and V-ATPases by mTORC1The EMBO Journal, 2011
- The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensationTrends in Biochemical Sciences, 2011
- Lysosomal accumulation of mTOR is enhanced by rapamycinHistochemistry and Cell Biology, 2010
- Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1Molecular Cell, 2010
- Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 MutationsCell, 2010
- Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino AcidsCell, 2010
- The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK–ERK pathway to late endosomesThe EMBO Journal, 2009
- Autophagy in the Pathogenesis of DiseaseCell, 2008