title: HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis.
abstract: Adult 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.
authors: Department of Animal and Avian Sciences and Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors: Carine
authors: C
authors: White
authors: Xiaojing
authors: X
authors: Yuan
authors: Paul J
authors: PJ
authors: Schmidt
authors: Erica
authors: E
authors: Bresciani
authors: Tamika K
authors: TK
authors: Samuel
authors: Dean
authors: D
authors: Campagna
authors: Caitlin
authors: C
authors: Hall
authors: Kevin
authors: K
authors: Bishop
authors: Monica L
authors: ML
authors: Calicchio
authors: Ariane
authors: A
authors: Lapierre
authors: Diane M
authors: DM
authors: Ward
authors: Paul
authors: P
authors: Liu
authors: Mark D
authors: MD
authors: Fleming
authors: Iqbal
authors: I
authors: Hamza
mesh_terms: D000818:Animals; D001692:Biological Transport; D004912:Erythrocytes / Q000166:cytology* / Q000378:metabolism; D017930:Genes, Reporter; D057809:HEK293 Cells; D006418:Heme / Q000378:metabolism*; D006420:Hemeproteins / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D012157:Mononuclear Phagocyte System / Q000166:cytology; D020125:Mutation, Missense / Q000235:genetics; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: C546603:HRG-1 protein, mouse; D006420:Hemeproteins; D012333:RNA, Messenger; C546602:SLC48A1 protein, human; D006418:Heme; D007501:Iron
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