Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy
Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy
复制标题
DOI：
10.1038/ncb2536
复制
发表时间：
2012-08-01
影响因子：
21.3
通讯作者：
Coffer, Paul J.
中科院分区：
文献类型：
--
作者：
van der Vos, Kristan E.;Eliasson, Pernilla;Coffer, Paul J.
PI(3)K-PKB-FOXO 信号网络为细胞增殖、存活和应激抵抗的调节提供了主要的细胞内中枢。在这里，我们报告了 FOXO 转录因子通过调节细胞内谷氨酰胺水平来调节自噬的意想不到的作用。为了确定该网络的转录目标，我们在关键组件 PI(3)K、PKB/Akt、FOXO3 和 FOXO4 的条件激活后进行了全局转录分析。使用该途径方法，我们确定谷氨酰胺合成酶受 PI(3)K-PKB-FOXO 信号传导的转录调节。 FOXO 的条件激活也导致谷氨酰胺产量水平增加。 FOXO 激活通过阻止 mTOR 以谷氨酰胺合成酶依赖性方式易位至溶酶体膜，从而抑制 mTOR。通过 LC3 脂化、p62 降解和多种自噬体标记物的荧光成像测量，这导致自噬水平增加。抑制 FOXO3 介导的自噬会增加细胞凋亡的水平，表明 FOXO3 介导的谷氨酰胺合成酶表达诱导自噬对于细胞存活很重要。这些发现揭示了一个生长因子响应网络，可以通过调节谷氨酰胺代谢来直接调节自噬。
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 inregulating 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.