9. Amino acids and autophagy: New insights into the role of GCN2-eIF2α signalling

Along with variations in the availability of essential amino acids (IAAs) in the diet, the body can experience significant changes in their concentrations in pathological conditions associated with acute and systemic inflammation, such as certain cancers or sepsis.
To cope with these fluctuations, adaptation mechanisms are triggered, such as the modulation of tissue proteolysis levels. At the molecular level, these adaptation mechanisms rely on signaling pathways, such as the GCN2-eIF2α-ATF4 and mTORC1 pathways.
Using a cellular model, we observed that deficiency in a single IAA, leucine, induces a rapid increase in proteolytic levels. We showed that this effect results from an increase in autophagic flux in a manner dependent on GCN2, the eIF2α kinase capable of detecting IAA deficiencies [1]. Specifically, leucine deficiency causes short-term increased mobilization of the autophagy induction step associated with an increase in the number of autophagosomes, both in vitro and in vivo in mouse liver. Using genetically modified cell models, we showed that GCN2 activation and eIF2α phosphorylation are required for these effects, but not ATF4 [1]. Our previous results had highlighted a role for this pathway in the activation of autophagy gene transcription in an ATF4-dependent manner [2]. Our new data reveal that GCN2 also plays a major short-term role in the mobilization steps of the autophagic process in response to the deficiency of an IAA such as leucine.

DOI : 10.1080/27694127.2022.2049045

Contact : Anne-Catherine Maurin - Pierre Fafournoux