Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells.
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.
Ohgami
Robert S
RS
Department of Pathology Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Campagna
Dean R
DR
Greer
Eric L
EL
Antiochos
Brendan
B
McDonald
Alice
A
Chen
Jing
J
Sharp
John J
JJ
Fujiwara
Yuko
Y
Barker
Jane E
JE
Fleming
Mark D
MD
D000595:Amino Acid Sequence; D018798:Anemia, Iron-Deficiency / Q000378:metabolism*; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D011992:Endosomes; D004912:Erythrocytes / Q000201:enzymology*; D038181:FMN Reductase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting; D007501:Iron / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010088:Oxidoreductases; D012190:Retroviridae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions; D014168:Transferrin / Q000378:metabolism*
D000951:Antigens, Neoplasm; D014168:Transferrin; D007501:Iron; D010088:Oxidoreductases; C432763:STEAP1 protein, human; D038181:FMN Reductase; C023903:ferric citrate iron reductase