The amino acid sensor GCN2 controls red blood cell life cycle and iron metabolism through regulation of tissue resident macrophages

GCN2 (General Control Nonderepressible 2) is a serine/threonine-protein kinase that controls mRNA translation in response to amino acid availability. Here we show that production and clearance of erythrocytes are controlled by GCN2. Our data highlight the importance of tissue-resident macrophages as the primary cell type mediating this effect. During different stress conditions, such as hemolysis, amino acid deficiency or hypoxia, GCN2 knockout (GCN2-/-) mice displayed resistance to anemia as compared to wild-type (GCN2+/+) mice. GCN2-/- liver macrophages display defective erythrophagocytosis and lysosome maturation. Molecular analysis of GCN2-/- cells indicates that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating RBC clearance and iron recycling. We performed NRF2 (Nfe2l2) ChIP-seq experiments in both WT and GCN2 KO MEFs with or without leucine deprivation. Overall design: WT and GCN2 KO MEFs were cultured in DMEM with or without Leucine for 24h prior to crosslinking and NRF2 ChIPs.