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Cited by 404Iron Metabolism and DisordersHemoglobin structure and functionErythrocyte Function and Pathophysiology

A Heme Export Protein Is Required for Red Blood Cell Differentiation and Iron Homeostasis

Keel, Siobán B., Doty, Raymond T., Yang, Zhantao, Quigley, John G., Chen, Jing, Knoblaugh, Sue, Kingsley, Paul D., De Domenico, Ivana +4 more·2008·Science
DOI 10.1126/science.1151133
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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.

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Crossref · 10.1126/science.1151133

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  • Macrophages possess the heme exporter Flvcr and its genetic deletion results in RPM iron overload.

    “At the cell surface membrane, macrophages possess the heme exporter Flvcr and its genetic deletion results in RPM iron overload [108].”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [108]

  • Targeted disruption of the mouse gene encoding FLVCR demonstrated the importance of this protein in vivo.

    “Targeted disruption of the mouse gene encoding FLVCR demonstrated the importance of this protein in vivo.21”

    From Forging a field: the golden age of iron biology. (2008) · cites this paper as [21]

  • When the FLVCR gene was inactivated after birth, the animals developed severe, macrocytic anemia, implying that heme export is important for normal erythropoiesis.

    “When the FLVCR gene was inactivated after birth the animals developed severe, macrocytic anemia, implying that heme export is important for normal erythropoiesis.”

    From Forging a field: the golden age of iron biology. (2008) · cites this paper as [21]

  • FLVCR-null mice had a failure of definitive erythropoiesis, resulting in fetal demise.

    “FLVCR-null mice had a failure of definitive erythropoiesis, resulting in fetal demise.”

    From Forging a field: the golden age of iron biology. (2008) · cites this paper as [21]

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Authors
Keel, S. B., Doty, R. T., Yang, Z., Quigley, J. G., Chen, J., Knoblaugh, S., Kingsley, P. D., De Domenico, I., Vaughn, M. B., Kaplan, J., Palis, J., & Abkowitz, J. L.
Affiliations
  • Division of Hematology, University of Washington, Seattle, WA 98195, USA.
  • University of Washington (US)
Corresponding author
  • Doty, Raymond T.
  • Quigley, John G.
  • Abkowitz, Janis L.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2008-02-08
Volume
319
Issue
5864
Pages
825-828
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1151133
OpenAlex
W1977605312
Cited by
404
References
24
Citations by year
2026: 12 · 2025: 13 · 2024: 15 · 2023: 15 · 2022: 20 · 2021: 15 · 2020: 23 · 2019: 14 · 2018: 28 · 2017: 27 · 2016: 15 · 2015: 23 · 2014: 28 · 2013: 20 · 2012: 31
FWCI
22.16
Type
journal article
Language
en
Open access
closed
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
  • Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
Keywords
heme export, erythropoiesis, iron homeostasis, Diamond-Blackfan anemia, macrocytic anemia, senescent red blood cells, hepatic iron, heme toxicity
MeSH terms
Animals, Erythroblasts, Erythropoiesis, Heme, Homeostasis, Iron, Macrophages, Receptors, Virus, Red-Cell Aplasia, Pure, Embryo Loss, Hepatocytes, Antimicrobial Cationic Peptides, Membrane Transport Proteins, Anemia, Diamond-Blackfan, Embryonic Development, Mice, Hepcidins

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