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

2022; National Academy of Sciences; Volume: 119; Issue: 35 Linguagem: Inglês

10.1073/pnas.2121251119

1091-6490

Phoenix Toboz, Mehdi Amiri, Negar Tabatabaei, Catherine R. Dufour, Seung Hyeon Kim, Carine Fillebeen, Charles Ayemoba, Arkady Khoutorsky, Manfred Nairz, Lijian Shao, Kostandin V. Pajcini, Ki-Wook Kim, Vincent Giguère, Regiana L. Oliveira, Marco Constante, Manuela M. Santos, Carlos R. Morales, Kostas Pantopoulos, Nahum Sonenberg, Sandra Pinho, Soroush Tahmasebi,

RNA regulation and disease

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.