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The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis

Agnes Roczniak-Ferguson1, Constance S Petit, Florian Froehlich

  • 1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.

Science Signaling
|June 14, 2012
PubMed

Insights

Cellular lysosomes adjust function via mTORC1 and transcription factor TFEB. Adequate lysosomal activity retains TFEB in cytoplasm; inhibited function moves TFEB to the nucleus, promoting lysosome biogenesis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Lysosomes are critical for cellular waste removal and homeostasis.
  • Lysosomal capacity must dynamically adapt to cellular demands.
  • Regulation of lysosomal function is essential for maintaining cellular health.

Purpose of the Study:

  • To investigate the interaction between mTORC1 and TFEB in lysosomal regulation.
  • To elucidate the mechanism controlling TFEB localization and activity.
  • To understand how cellular need influences lysosome biogenesis.

Main Methods:

  • Identified protein-protein interactions using co-immunoprecipitation.
  • Assessed protein phosphorylation status via Western blotting.
  • Tracked transcription factor translocation using immunofluorescence microscopy.

Main Results:

  • Lysosome-localized mTORC1 phosphorylates TFEB, promoting 14-3-3 binding and cytoplasmic retention.
  • Inhibition of lysosomal function reduces TFEB phosphorylation, releasing it from 14-3-3 binding.
  • Reduced TFEB-14-3-3 interaction facilitates TFEB nuclear translocation, activating lysosomal biogenesis genes.

Conclusions:

  • TFEB is a direct target of mTORC1 signaling in response to lysosomal activity.
  • This mechanism links lysosomal function to the transcriptional control of lysosome biogenesis.
  • Related factors MITF and TFE3 may utilize similar regulatory pathways.

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