Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy

Nat Cell Biol. 2012 Aug;14(8):829-37. doi: 10.1038/ncb2536. Epub 2012 Jul 22.

Abstract

The PI(3)K-PKB-FOXO signalling network provides a major intracellular hub for the regulation of cell proliferation, survival and stress resistance. Here we report an unexpected role for FOXO transcription factors in regulating autophagy by modulating intracellular glutamine levels. To identify transcriptional targets of this network, we performed global transcriptional analyses after conditional activation of the key components PI(3)K, PKB/Akt, FOXO3 and FOXO4. Using this pathway approach, we identified glutamine synthetase as being transcriptionally regulated by PI(3)K-PKB-FOXO signalling. Conditional activation of FOXO also led to an increased level of glutamine production. FOXO activation resulted in mTOR inhibition by preventing the translocation of mTOR to lysosomal membranes in a glutamine-synthetase-dependent manner. This resulted in an increased level of autophagy as measured by LC3 lipidation, p62 degradation and fluorescent imaging of multiple autophagosomal markers. Inhibition of FOXO3-mediated autophagy increased the level of apoptosis, suggesting that the induction of autophagy by FOXO3-mediated glutamine synthetase expression is important for cellular survival. These findings reveal a growth-factor-responsive network that can directly modulate autophagy through the regulation of glutamine metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Autophagy*
  • Base Sequence
  • Blotting, Western
  • Cell Proliferation
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation
  • Glutamate Synthase / genetics
  • Glutamate Synthase / metabolism
  • Glutamine / metabolism*
  • Humans
  • Mice
  • Microarray Analysis
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Polymerase Chain Reaction
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Sequence Alignment
  • Signal Transduction

Substances

  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Glutamine
  • Glutamate Synthase
  • Phosphatidylinositol 3-Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Protein-Serine-Threonine Kinases