Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, MA, USA.
Autophagy. 2012 Dec;8(12):1862-4. doi: 10.4161/auto.22152. Epub 2012 Sep 20.
Activation of the PI3K-AKT1-FOXO module by growth factors increases survival and stress resistance. We identified the gene encoding glutamine synthetase (GLUL, glutamate-ammonia ligase) as a novel transcriptional target of this signaling cascade. Growth factor removal increases glutamine synthetase expression and activity through activation of FOXO transcription factors. Surprisingly, increased levels of glutamine synthetase inhibit MTOR signaling by blocking its lysosomal translocation. Furthermore, FOXO activation induces autophagosome formation and autophagic flux in a glutamine synthetase-dependent manner. This may be important for maintaining cell survival during conditions of growth factor and nutrient deprivation since inhibition of autophagy induces cell death. These studies reveal that glutamine metabolism can play an important regulatory role in the regulation of autophagy by growth factor signaling. In addition, the induction of autophagy by FOXO-mediated glutamine synthetase expression might contribute to the tumor suppressive function of FOXOs.
生长因子激活 PI3K-AKT1-FOXO 模块可增加细胞存活和应激抗性。我们发现编码谷氨酰胺合成酶（GLUL，谷氨酸-氨连接酶）的基因是该信号级联的一个新的转录靶标。生长因子去除通过激活 FOXO 转录因子增加谷氨酰胺合成酶的表达和活性。令人惊讶的是，谷氨酰胺合成酶水平的增加通过阻止 MTOR 的溶酶体易位来抑制 MTOR 信号。此外，FOXO 激活以谷氨酰胺合成酶依赖的方式诱导自噬体形成和自噬流。在生长因子和营养缺乏的情况下，这对于维持细胞存活可能很重要，因为自噬的抑制会诱导细胞死亡。这些研究表明，谷氨酰胺代谢可以通过生长因子信号在自噬的调节中发挥重要的调节作用。此外，FOXO 介导的谷氨酰胺合成酶表达诱导的自噬可能有助于 FOXOs 的肿瘤抑制功能。
