title: Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy.
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.
authors: Department of Immunology, University Medical Center Utrecht, Utrecht 3584CX, The Netherlands.
authors: Kristan E
authors: KE
authors: van der Vos
authors: Pernilla
authors: P
authors: Eliasson
authors: Tassula
authors: T
authors: Proikas-Cezanne
authors: Stephin J
authors: SJ
authors: Vervoort
authors: Ruben
authors: R
authors: van Boxtel
authors: Marrit
authors: M
authors: Putker
authors: Iris J
authors: IJ
authors: van Zutphen
authors: Mario
authors: M
authors: Mauthe
authors: Sebastian
authors: S
authors: Zellmer
authors: Cornelieke
authors: C
authors: Pals
authors: Liesbeth P
authors: LP
authors: Verhagen
authors: Marian J A
authors: MJ
authors: Groot Koerkamp
authors: A Koen
authors: AK
authors: Braat
authors: Tobias B
authors: TB
authors: Dansen
authors: Frank C
authors: FC
authors: Holstege
authors: Rolf
authors: R
authors: Gebhardt
authors: Boudewijn M
authors: BM
authors: Burgering
authors: Paul J
authors: PJ
authors: Coffer
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001343:Autophagy; D001483:Base Sequence; D015153:Blotting, Western; D049109:Cell Proliferation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005970:Glutamate Synthase / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005970:Glutamate Synthase; D005973:Glutamine; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; C499517:FOXO3 protein, human