The amino acid sensor GCN2 controls red blood cell clearance and iron metabolism through regulation of liver macrophages

GCN2 (general control nonderepressible 2) is a serine/threonine-protein kinase that controls messenger RNA translation in response to amino acid availability and ribosome stalling. Here, we show that GCN2 controls erythrocyte clearance and iron recycling during stress. Our data highlight the importance of liver macrophages as the primary cell type mediating these effects. During different stress conditions, such as hemolysis, amino acid deficiency or hypoxia, GCN2 knockout (GCN2(-/-)) mice displayed resistance to anemia compared with wild-type (GCN2(+/+)) mice. GCN2(-/-) liver macrophages exhibited defective erythrophagocytosis and lysosome maturation. Molecular analysis of GCN2(-/-) cells demonstrated that the ATF4-NRF2 pathway is a critical downstream mediator of GCN2 in regulating red blood cell clearance and iron recycling.