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Cited by 779Iron Metabolism and DisordersIron and Steelmaking ProcessesNeurological diseases and metabolism

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

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Ohgami, Robert S, Campagna, Dean R, Greer, Eric L, Antiochos, Brendan, McDonald, Alice, Chen, Jing, Sharp, John J, Fujiwara, Yuko +2 more·2005·Nature Genetics
DOI 10.1038/ng1658PMC PMC2156108
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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 F(420)H(2):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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  • The freed ferric iron is reduced to Fe2+ by STEAP3 and shuttled into the cytosol from the endosome by DMT1.

    “The freed ferric iron is then reduced to its bio-active ferrous form, Fe2+ by the ferrireductase STEAP3 (six-transmembrane epithelial antigen of prostate 3) and shuttled into the cytosol from the endosome by DMT1 (Fleming et al., 1997; Gunshin et al., 1997; Ohgami et al., 2005; Figure 1).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Ohgami et al., 2005

  • Dmt1 only accepts ferrous iron along with other divalent cations and co-localizes with an iron reductase.

    “At either location, Dmt1 only accepts ferrous iron along with other divalent cations, such as copper or manganese, and co-localizes with an iron reductase [152, 177].”

    From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [177]

  • Liberated inorganic iron is reduced by the ferrireductase STEAP3 to Fe2+, which is the substrate for transmembrane transport by DMT1.

    “Liberated inorganic iron is then reduced by the ferrireductase STEAP3 to Fe 2ϩ , 10 which is the substrate for transmembrane transport by divalent metal transporter 1 (DMT1 or SLC11A2, formerly called NRAMP2, DCT1).”

    From Forging a field: the golden age of iron biology. (2008) · cites this paper as [10]

  • Both STEAP3 and DMT1 were discovered through positional cloning of genes altered in rodents carrying spontaneous mutations impairing iron transport.

    “Both STEAP3 and DMT1 were discovered through positional cloning of genes altered in rodents carrying spontaneous mutations impairing iron transport.10,11”

    From Forging a field: the golden age of iron biology. (2008) · cites this paper as [10]

  • Amino acid and serum depletion activate autophagy, resulting in ferritin degradation, which sensitized cells to H2O2-induced oxidative stress.

    “Amino acid and serum depletion activate autophagy, resulting in ferritin degradation, which sensitized cells to H2O2-induced oxidative stress because of an increased “labile iron” pool, which caused ROS production via the Fenton reaction (226).”

    From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [226]

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Authors
Ohgami, R. S., Campagna, D. R., Greer, E. L., Antiochos, B., McDonald, A., Chen, J., Sharp, J. J., Fujiwara, Y., Barker, J. E., & Fleming, M. D.
Affiliations
  • Harvard University (US)
  • Takeda Oncology (United States) (US)
  • Brigham and Women's Hospital (US)
  • Emory University (US)
  • Boston Children's Hospital (US)
  • Jackson Laboratory (US)
Corresponding author
Fleming, Mark D
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2005-10-16
Volume
37
Issue
11
Pages
1264-1269
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng1658
PMC
PMC2156108
OpenAlex
W2069774708
Cited by
775
References
33
Citations by year
2026: 35 · 2025: 48 · 2024: 48 · 2023: 60 · 2022: 52 · 2021: 47 · 2020: 41 · 2019: 28 · 2018: 41 · 2017: 23 · 2016: 22 · 2015: 31 · 2014: 28 · 2013: 30 · 2012: 45
FWCI
16.60
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL074247)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK049216, R01DK027726)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Physical Sciences › Engineering › Mechanical Engineering › Iron and Steelmaking Processes
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
ferrireductase, STEAP3, erythroid cells, iron deficiency anemia, positional cloning, red blood cell precursors
MeSH terms
Amino Acid Sequence, Animals, Antigens, Neoplasm, Cells, Cultured, Erythrocytes, Female, Iron, Kidney, Male, Mice, Mutant Strains, Molecular Sequence Data, Oxidoreductases, Endosomes, Retroviridae, Subcellular Fractions, Transferrin, Blotting, Western, Sequence Homology, Amino Acid, Gene Targeting, Anemia, Iron-Deficiency, FMN Reductase, Mice

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