HRG1 Is Essential for Heme Transport from the Phagolysosome of Macrophages during Erythrophagocytosis

SummaryAdult humans have about 25 trillion red blood cells (RBCs), and each second we recycle about 5 million RBCs by erythrophagocytosis (EP) in macrophages of the reticuloendothelial system. Despite the central role for EP in mammalian iron metabolism, the molecules and pathways responsible for heme trafficking during EP remain unknown. Here, we show that the mammalian homolog of HRG1, a transmembrane heme permease in C. elegans, is essential for macrophage iron homeostasis and transports heme from the phagolysosome to the cytoplasm during EP. HRG1 is strongly expressed in macrophages of the reticuloendothelial system and specifically localizes to the phagolysosomal membranes during EP. Depletion of Hrg1 in mouse macrophages causes attenuation of heme transport from the phagolysosomal compartment. Importantly, missense polymorphisms in human HRG1 are defective in heme transport. Our results reveal HRG1 as the long-sought heme transporter for heme-iron recycling in macrophages and suggest that genetic variations in HRG1 could be modifiers of human iron metabolism.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (246 K)Download as PowerPoint slideHighlights► Humans have about 25 trillion RBCs, each containing over a billion heme moieties ► Five million senescent RBCs are recycled per second by erythrophagocytosis in macrophages to make new RBCs ► HRG1, the mammalian homolog of C. elegans heme transporter, recycles heme-iron from the macrophage phagolysosome ► Missense polymorphisms in human HRG1 may be genetic modifiers of iron metabolism