A heme export protein is required for red blood cell differentiation and iron homeostasis.
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.
Keel
Siobán B
SB
Division of Hematology, University of Washington, Seattle, WA 98195, USA.
Doty
Raymond T
RT
Yang
Zhantao
Z
Quigley
John G
JG
Chen
Jing
J
Knoblaugh
Sue
S
Kingsley
Paul D
PD
De Domenico
Ivana
I
Vaughn
Michael B
MB
Kaplan
Jerry
J
Palis
James
J
Abkowitz
Janis L
JL
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
D023181:Antimicrobial Cationic Peptides; C526650:Flvcr1 protein, mouse; D064451:Hepcidins; D026901:Membrane Transport Proteins; D011991:Receptors, Virus; D006418:Heme; D007501:Iron