The GCN2 kinase activates early events of autophagy

Autophagy Session : Selected oral communication, Poster N°37Organizing Committee: Chairs: Didier Attaix, Lydie Combaret and Daniel TaillandierThe protein kinase GCN2 detects free tRNA during stresses of essential amino acid (EAA) deficiencies and triggers an adaptive cell response by phosphorylating eIF2α. This leads to both a decrease in protein synthesis and the emergence of an ATF4-dependent gene expression program. Our previous work provided evidence that the GCN2/p-eIF2α/ATF4 pathway plays a major role in macro-autophagy by upregulating the expression of a number of autophagy-related genes at the transcriptional level, thereby contributing to expand the process over the long term. Here, we aimed at determining whether GCN2 could be involved in the early steps of activation of the autophagic process. Our data showed that autophagy was activated within the first hour of a single EAA deficiency in both cultured cells and mouse liver, a response that required GCN2. Furthermore, we observed that the phosphorylation of eIF2α contributed to this adaptive upregulation of autophagy whereas ATF4 was dispensable. Importantly, by using experimental conditions to activate GCN2 without affecting mTORC1 activity, our data showed that the GCN2-dependent activation of autophagy occurs without requiring concomitant mTORC1 inhibition. Overall these results highlighted that the GCN2/p-eIF2α signaling was sufficient to activate early stages of autophagy upregulation