Macrophage-specific LAMTOR2 deletion disrupts systemic iron homeostasis in mice.

Abstract

At the center of iron homeostasis, macrophages play a crucial role by phagocytosing senescent erythrocytes while nursing erythrocyte progenitors. A major route of cellular iron acquisition occurs via transferrin receptor 1 (TFR1)-mediated endocytosis of transferrin-bound iron, a process that critically depends on endosomal trafficking. The late endosomal adaptor LAMTOR2 regulates mTORC1/MAPK signaling and endosomal traffic, yet its role in macrophage iron handling is unknown. Here we show that mice lacking LAMTOR2 in myeloid cells develop iron-restricted erythropoiesis, characterized by reduced hepcidin and bone marrow iron deficiency along with increased erythrophagocytosis and splenic iron accumulation, and compensatory extramedullary erythropoiesis. Macrophages deficient in LAMTOR2 display markedly reduced TFR1 protein and impaired transferrin-mediated iron uptake. Mechanistically, loss of LAMTOR2 results in shifting of TFR1 to lysosomes which were hyperacidified when compared to control cells. Pharmacological inhibition of lysosomal acidification but not of proteasomal degradation restores TFR1 in LAMTOR2-deficient macrophages. Our study collectively identifies a novel role for the LAMTOR2 complex in preventing TFR1 degradation and potentially facilitating iron delivery from bone marrow macrophages to erythroid progenitors. We demonstrate that LAMTOR2-dependent endosomal trafficking is a critical, previously unrecognized mechanism that stabilizes the transferrin receptor, enables essential iron recycling in macrophages and ultimately sustains systemic iron homeostasis.