Glutamine metabolism links growth factor signaling to the regulation of autophagy.

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.