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Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells

Nature Genetics volume 37, pages 1264–1269 (2005)Cite this article

Abstract

The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell precursors. A deficiency in iron acquisition by red blood cells leads to hypochromic, microcytic anemia. Using a positional cloning strategy, we identified a gene, six-transmembrane epithelial antigen of the prostate 3 (Steap3), responsible for the iron deficiency anemia in the mouse mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tf-bound iron uptake. Steap3 shares homology with F420H2:NADP+ oxidoreductases found in archaea and bacteria, as well as with the yeast FRE family of metalloreductases. Overexpression of Steap3 stimulates the reduction of iron, and mice lacking Steap3 are deficient in erythroid ferrireductase activity. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.

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Figure 1: nm1054 physical map and BAC complementation.
Figure 2: Steap3 mRNA expression.
Figure 3: Steap3 subcellular localization.
Figure 4: Somatic complementation of nm1054-associated anemia in bone marrow chimeras.
Figure 5: Hematologic data from Steap3nm1054 and Steap3-null mice.
Figure 6: Structure of the Steap family and function of Steap3.

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Acknowledgements

We thank L. Lee, H. Gunshin, N. Andrews, E. Neufeld and members of the laboratories of N. Andrews and E. Neufeld for ongoing support and criticism and N. Stokes and T. Borjeson for technical support. This work was supported by the Pew Biomedical Scholars Program (M.D.F) and grants from the US National Institutes of Health (M.D.F. and J.E.B.). Transgenic core facilities were supported by a grant from the US National Institutes of Health.

Author information

Author notes

  1. Jing Chen

    Present address: Winship Cancer Institute, Emory University, 1365-C, Clifton Rd. N.E., Atlanta, Georgia, 30322, USA

  2. John J Sharp

    Present address: Center for Comparative Medicine 600D, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

Authors and Affiliations

  1. Department of Pathology Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Robert S Ohgami, Dean R Campagna, Eric L Greer, Brendan Antiochos & Mark D Fleming

  2. Medical Scientist Training Program, Harvard Medical School, Tosteson Medical Education Center, Room 168, 260 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Robert S Ohgami

  3. Millennium Pharmaceuticals, 45-2 Sidney Street, Cambridge, 01239, Massachusetts, USA

    Alice McDonald

  4. Division of Hematology, Brigham and Women's Hospital, 1 Blackfan Circle, Boston, 02115, Massachusetts, USA

    Jing Chen

  5. The Jackson Laboratory, 600 Main Street, Bar Harbor, 04609, Maine, USA

    John J Sharp & Jane E Barker

  6. Division of Hematology and Howard Hughes Medical Institute, Children's Hospital, 1 Blackfan Circle, Boston, 02115, Massachusetts, USA

    Yuko Fujiwara

  7. Winship Cancer Institute, Emory University, 1365-C, Clifton Rd. N.E., Atlanta, Georgia, 30322, USA

    John J Sharp

  8. Center for Comparative Medicine 600D, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Jing Chen

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Supplementary information

Supplementary Fig. 1

Recombination map of the nm1054 locus. (PDF 96 kb)

Supplementary Fig. 2

Steap3 gene targeting strategy. (PDF 141 kb)

Supplementary Fig. 3

Multiple sequence alignment of the Steaps. (PDF 94 kb)

Supplementary Table 1

Hematological data in Steap3 mutant and control mice. (PDF 61 kb)

Supplementary Table 2

Iron status of 8-week-old Steap3 mutant and control mice. (PDF 51 kb)

Supplementary Table 3

Quantitative real-time PCR primers. (PDF 28 kb)

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Ohgami, R., Campagna, D., Greer, E. et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 37, 1264–1269 (2005). https://doi.org/10.1038/ng1658

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