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

Sci. Signal., 12 June 2012
Vol. 5, Issue 228, p. ra42
DOI: 10.1126/scisignal.2002790

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

  1. Agnes Roczniak-Ferguson1,2,
  2. Constance S. Petit1,2,
  3. Florian Froehlich1,
  4. Sharon Qian1,2,
  5. Jennifer Ky1,2,
  6. Brittany Angarola1,2,
  7. Tobias C. Walther1, and
  8. Shawn M. Ferguson1,2,*
  1. 1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
  2. 2Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
  1. *To whom correspondence should be addressed. E-mail: shawn.ferguson{at}yale.edu

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.

Citation:

A. Roczniak-Ferguson, C. S. Petit, F. Froehlich, S. Qian, J. Ky, B. Angarola, T. C. Walther, and S. M. Ferguson, The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis. Sci. Signal. 5, ra42 (2012).

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