The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis.
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.
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
Agnes
A
Roczniak-Ferguson
Constance S
CS
Petit
Florian
F
Froehlich
Sharon
S
Qian
Jennifer
J
Ky
Brittany
B
Angarola
Tobias C
TC
Walther
Shawn M
SM
Ferguson
D048948:14-3-3 Proteins / Q000378:metabolism; D000704:Analysis of Variance; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D018613:Microscopy, Confocal; D046912:Multiprotein Complexes; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D048948:14-3-3 Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D046912:Multiprotein Complexes; D011506:Proteins; C069203:TFE3 protein, human; C064972:TFEB protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases