title: A heme export protein is required for red blood cell differentiation and iron homeostasis.
abstract: Hemoproteins are critical for the function and integrity of aerobic cells. However, free heme is toxic. Therefore, cells must balance heme synthesis with its use. We previously demonstrated that the feline leukemia virus, subgroup C, receptor (FLVCR) exports cytoplasmic heme. Here, we show that FLVCR-null mice lack definitive erythropoiesis, have craniofacial and limb deformities resembling those of patients with Diamond-Blackfan anemia, and die in midgestation. Mice with FLVCR that is deleted neonatally develop a severe macrocytic anemia with proerythroblast maturation arrest, which suggests that erythroid precursors export excess heme to ensure survival. We further demonstrate that FLVCR mediates heme export from macrophages that ingest senescent red cells and regulates hepatic iron. Thus, the trafficking of heme, and not just elemental iron, facilitates erythropoiesis and systemic iron balance.
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Siobán B
authors.initials: SB
authors.lastname: Keel
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Doty
authors.forename: Zhantao
authors.initials: Z
authors.lastname: Yang
authors.forename: John G
authors.initials: JG
authors.lastname: Quigley
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Sue
authors.initials: S
authors.lastname: Knoblaugh
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kingsley
authors.forename: Ivana
authors.initials: I
authors.lastname: De Domenico
authors.forename: Michael B
authors.initials: MB
authors.lastname: Vaughn
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
authors.forename: James
authors.initials: J
authors.lastname: Palis
authors.forename: Janis L
authors.initials: JL
authors.lastname: Abkowitz
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000097:blood / Q000473:pathology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D020964:Embryo Loss; D047108:Embryonic Development; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis; D006418:Heme / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D064451:Hepcidins; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D012010:Red-Cell Aplasia, Pure / Q000097:blood / Q000473:pathology
chemical_list: D023181:Antimicrobial Cationic Peptides; C526650:Flvcr1 protein, mouse; D064451:Hepcidins; D026901:Membrane Transport Proteins; D011991:Receptors, Virus; D006418:Heme; D007501:Iron