MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB

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Reconstitution of Msp1 Extraction Activity with Fully Purified Components
05:52

Reconstitution of Msp1 Extraction Activity with Fully Purified Components

Published on: August 10, 2021

Jose A Martina1, Yong Chen, Marjan Gucek

  • 1Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD USA.

Autophagy
|May 12, 2012
PubMed

Insights

Mammalian target of rapamycin complex 1 (MTORC1) controls autophagy gene expression by regulating the nuclear entry of transcription factor EB (TFEB). MTORC1 inhibition promotes TFEB nuclear translocation, boosting autophagy and lysosomal gene transcription for cellular homeostasis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mammalian target of rapamycin (MTOR) pathway regulates cell growth and proliferation.
  • MTOR complex 1 (MTORC1) inhibition induces autophagy, a cellular degradation process, by affecting the ULK protein kinase complex.
  • The role of MTORC1 in regulating the expression of autophagy-related genes remains unclear.

Purpose of the Study:

  • To investigate the role of MTORC1 in the transcriptional regulation of autophagy and lysosomal genes.
  • To elucidate the mechanism by which MTORC1 influences the activity of transcription factor EB (TFEB).

Main Methods:

  • Utilized pharmacological and genetic inhibition of MTORC1.
  • Assessed TFEB phosphorylation, cytosol-to-nucleus translocation, and association with YWHA (14-3-3) proteins.
  • Analyzed TFEB's transcriptional activity on autophagy and lysosomal genes.
  • Investigated TFEB interaction with the LAMTOR/RRAG/MTORC1 complex on endosomal membranes.

Main Results:

  • MTORC1 directly regulates the nuclear localization and activity of transcription factor EB (TFEB).
  • Under nutrient-rich conditions, MTORC1 phosphorylates TFEB at Ser211, promoting its cytosolic retention via YWHA (14-3-3) binding.
  • Inhibition of MTORC1 leads to TFEB dephosphorylation, dissociation from YWHA, and translocation to the nucleus.
  • Nuclear TFEB enhances the transcription of genes involved in autophagy and lysosomal function, and associates with late endosomal/lysosomal membranes.

Conclusions:

  • MTORC1 plays a novel role in maintaining cellular homeostasis by transcriptionally controlling autophagy.
  • The MTORC1-TFEB axis represents a critical regulatory mechanism linking nutrient status to the expression of autophagy and lysosomal genes.
  • This finding provides new insights into the regulation of cellular catabolic processes.

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