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

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 (RBC) precursors. A deficiency in RBC iron acquisition leads to a hypochromic, microcytic anemia. Using a positional cloning strategy, we have identified a gene, sixtransmembrane epithelial antigen of the prostate 3 (Steap3), which is responsible for the iron deficiency anemia in the murine mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, co-localizes 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. Altogether, these findings demonstrate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.Red blood cell precursors are uniquely dependent upon the transferrin (Tf) cycle to acquire iron in order to synthesize heme in amounts sufficient for hemoglobin production 1 . In the transferrin cycle, iron bound to transferrin (Tf) binds to the transferrin receptor (Tfr1), the complex is taken up by receptor-mediated endocytosis, and iron is released from Tf by endosomal acidification to be delivered to the cytoplasm by the divalent metal transporter 1 (Dmt1) 2-4 . Tf carries ferric iron (Fe 3+ ), whereas Dmt1 is selective for ferrous iron (Fe 2+ ) 4 . Therefore, iron must be reduced in the Tf cycle endosome. Despite functional evidence of such an activity, the molecular identity of this reductase is unknown. Recently, an ascorbatedependent b-type cytochrome ferrireductase, Dcytb (Cybrd1), expressed predominantly in the duodenum, was described 5 . However, Dcytb is not expressed highly in erythroid precursors, and Dcytb null mice have normal iron metabolism and normal hematologic parameters 6 . Such

Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice

“…One explanation for the microcytosis is that TSAP6 is a ferrireductase. 5 Our results suggest that there is an alternative explanation for the TSAP6À/À phenotype, namely the one provided by the above-discussed data on the localization of TSAP6 and the biological connection between the endosomal/TGN compartment and exosomes. The absence of TSAP6 causes a deregulation of these compartments, resulting in a severe deficiency in exosome formation delaying the maturation of bone marrow erythroblasts and peripheral blood reticulocytes, leading to smaller cells retaining the Tf-R instead of expelling it.…”

“…3 TSAP6 is part of a family of oxydoreductases with six transmembrane domains 4 and was recently identified as a ferrireductase (Steap3). 5 TSAP6 knockdown results in inhibition of apoptosis. 3 It binds to 3 and cooperates with Nix, a proapoptotic, BH3-only, Bcl2 familymember and Myt1 kinase, a negative regulator of the G 2 M transition.…”

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

“…In addition, all STEAP members contain a C-terminal ferric oxidoreductase. Thus, a role in cellular iron homeostasis is assumed for these proteins (16). However, in contrast to other STEAP proteins, STEAP1 does not facilitate iron uptake and reduction, suggesting another distinct function (7).…”

Renal Iron Metabolism

“…The TfR functions as a dimer, and each 90-kD monomer has a single transmembrane-spanning domain. Upon binding iron-bearing Tf, the TfR-Tf complex is internalized into an early endosome, where acidification facilitates release of Fe 3ϩ from Tf and a reductase reduces Fe 3ϩ to Fe 2ϩ (10), which then can be exported into cytosol by DMT-1 in the late endosomal/lysosomal compartment. A second TfR that is expressed mainly by hepatocytes, TfR2, is not regulated by intracellular iron levels and is unlikely to be important in renal iron metabolism (11).…”