title: Prion protein functions as a ferrireductase partner for ZIP14 and DMT1.
abstract: Excess circulating iron is stored in the liver, and requires reduction of non-Tf-bound iron (NTBI) and transferrin (Tf) iron at the plasma membrane and endosomes, respectively, by ferrireductase (FR) proteins for transport across biological membranes through divalent metal transporters. Here, we report that prion protein (PrP(C)), a ubiquitously expressed glycoprotein most abundant on neuronal cells, functions as a FR partner for divalent-metal transporter-1 (DMT1) and ZIP14. Thus, absence of PrP(C) in PrP-knock-out (PrP(-/-)) mice resulted in markedly reduced liver iron stores, a deficiency that was not corrected by chronic or acute administration of iron by the oral or intraperitoneal routes. Likewise, preferential radiolabeling of circulating NTBI with (59)Fe revealed significantly reduced uptake and storage of NTBI by the liver of PrP(-/-) mice relative to matched PrP(+/+) controls. However, uptake, storage, and utilization of ferritin-bound iron that does not require reduction for uptake were increased in PrP(-/-) mice, indicating a compensatory response to the iron deficiency. Expression of exogenous PrP(C) in HepG2 cells increased uptake and storage of ferric iron (Fe(3+)), not ferrous iron (Fe(2+)), from the medium, supporting the function of PrP(C) as a plasma membrane FR. Coexpression of PrP(C) with ZIP14 and DMT1 in HepG2 cells increased uptake of Fe(3+) significantly, and surprisingly, increased the ratio of N-terminally truncated PrP(C) forms lacking the FR domain relative to full-length PrP(C). Together, these observations indicate that PrP(C) promotes, and possibly regulates, the uptake of NTBI through DMT1 and Zip14 via its FR activity. Implications of these observations for neuronal iron homeostasis under physiological and pathological conditions are discussed.
authors: Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Ajai K
authors: AK
authors: Tripathi
authors: Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Swati
authors: S
authors: Haldar
authors: Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Juan
authors: J
authors: Qian
authors: School of Arts and Sciences, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Amber
authors: A
authors: Beserra
authors: Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Srinivas
authors: S
authors: Suda
authors: Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Ajay
authors: A
authors: Singh
authors: Department of physiology and Biophysics, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Ulrich
authors: U
authors: Hopfer
authors: Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Shu G
authors: SG
authors: Chen
authors: Department of Biochemistry, University at Buffalo.
authors: Michael D
authors: MD
authors: Garrick
authors: Department of Pathology, University of Chicago.
authors: Jerrold R
authors: JR
authors: Turner
authors: Department of Food Science and Human Nutrition, University of Florida, USA.
authors: Mitchell D
authors: MD
authors: Knutson
authors: Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors: Neena
authors: N
authors: Singh
mesh_terms: D000818:Animals; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000378:metabolism*; D038181:FMN Reductase / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D018345:Mice, Knockout; D018621:PrPC Proteins / Q000502:physiology*; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D038181:FMN Reductase; D007501:Iron; D018621:PrPC Proteins; D000099236:Solute Carrier Family 11, Member 2; C500556:SLC39A14 protein, mouse; C023903:ferric citrate iron reductase
keywords: DMT1; Ferrireductase; Iron; Liver; Prion protein; Zip proteins