New insights into the role of GCN2-eIF2alpha signaling in the regulation of autophagy

International audienceAlongside variations in the availability of dietary nutrients, the body may experience significant changes in amino acid profiles as a result of pathological conditions. For example, a number of diseases are associated with a catabolic state and deregulated amino acid homeostasis. To cope with fluctuations in essential amino acid (EAA) availability, mammals have evolved a broad spectrum of adaptive mechanisms. Among these, the kinase GCN2 is activated in cells undergoing EAA scarcities, thereby leading to the phosphorylation of eIF2alpha, a signaling node contributing to adaptation to stress [1]. The phosphorylation of eIF2alpha notably leads to protein synthesis reduction and initiates a gene expression program, mediated by the translationally upregulated transcription factor ATF4. We aimed at characterizing the role of GCN2-eIF2alpha signaling in the regulation of autophagy. In a cell model of deprivation of a single EAA, we observed that proteolysis was rapidly increased in response to leucine starvation, an effect that was mainly due to autophagy and dependent on GCN2. One-hour leucine deprivation upregulated autophagy in both cultured cells and in vivo in mouse liver, as reflected by an increase in [S278]-ATG16L1 phosphorylation and LC3B conversion, and decreased p62 protein level [2]. Using cells and mice with genetic ablation of Gcn2 as well as genetic reconstitution experiments in vitro, data showed that GCN2 was required for this upregulation of autophagy in response to short-term EAA deprivation. The phosphorylation of eIF2alpha was also required while the expression of ATF4 was not [2]. These results complete our previous data demonstrating that activation of the GCN2-eIF2alpha-ATF4 pathway is involved, for longer-term EAA deprivations, in upregulating the transcription of many autophagy genes [3]. Taken together, our data thus indicate that GCN2-eIF2alpha signaling plays an important role in the regulation of autophagy, by the way of both ATF4-mediated transcriptional upregulation of autophagy gene expression and ATF4-independent mechanisms. This should contribute to the adjustment of protein and AA homeostasis in response to EAA limitation. Our data contribute to define eIF2alpha signaling as an important regulator of autophagy during physiological stress and/or pathology