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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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.
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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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DOI: https://doi.org/10.1038/ng1658
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