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J Biol Chem
2012 Oct 05;28741:34032-43. doi: 10.1074/jbc.M112.367284.
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ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading.
Wang CY, Jenkitkasemwong S, Duarte S, Sparkman BK, Shawki A, Mackenzie B, Knutson MD.
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ZIP8 (SLC39A8) belongs to the ZIP family of metal-ion transporters. Among the ZIP proteins, ZIP8 is most closely related to ZIP14, which can transport iron, zinc, manganese, and cadmium. Here we investigated the iron transport ability of ZIP8, its subcellular localization, pH dependence, and regulation by iron. Transfection of HEK 293T cells with ZIP8 cDNA enhanced the uptake of (59)Fe and (65)Zn by 200 and 40%, respectively, compared with controls. Excess iron inhibited the uptake of zinc and vice versa. In RNA-injected Xenopus oocytes, ZIP8-mediated (55)Fe(2+) transport was saturable (K(0.5) of ∼0.7 μm) and inhibited by zinc. ZIP8 also mediated the uptake of (109)Cd(2+), (57)Co(2+), (65)Zn(2+) > (54)Mn(2+), but not (64)Cu (I or II). By using immunofluorescence analysis, we found that ZIP8 expressed in HEK 293T cells localized to the plasma membrane and partially in early endosomes. Iron loading increased total and cell-surface levels of ZIP8 in H4IIE rat hepatoma cells. We also determined by using site-directed mutagenesis that asparagine residues 40, 88, and 96 of rat ZIP8 are glycosylated and that N-glycosylation is not required for iron or zinc transport. Analysis of 20 different human tissues revealed abundant ZIP8 expression in lung and placenta and showed that its expression profile differs markedly from ZIP14, suggesting nonredundant functions. Suppression of endogenous ZIP8 expression in BeWo cells, a placental cell line, reduced iron uptake by ∼40%, suggesting that ZIP8 participates in placental iron transport. Collectively, these data identify ZIP8 as an iron transport protein that may function in iron metabolism.
Adams,
Hepatic zinc in hemochromatosis.
1991, Pubmed
Adams,
Hepatic zinc in hemochromatosis.
1991,
Pubmed Aydemir,
Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-gamma expression in activated human T cells.
2009,
Pubmed Aydemir,
The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice.
2012,
Pubmed Begum,
Mycobacterium bovis BCG cell wall and lipopolysaccharide induce a novel gene, BIGM103, encoding a 7-TM protein: identification of a new protein family having Zn-transporter and Zn-metalloprotease signatures.
2002,
Pubmed Besecker,
The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epithelia.
2008,
Pubmed Bierings,
Transferrin receptor expression and the regulation of placental iron uptake.
1991,
Pubmed Borgna-Pignatti,
Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine.
2004,
Pubmed Brissot,
Role of non-transferrin-bound iron in the pathogenesis of iron overload and toxicity.
2002,
Pubmed Chua,
Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis.
2004,
Pubmed Craven,
Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis.
1987,
Pubmed Dalton,
Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis.
2005,
Pubmed Eide,
A novel iron-regulated metal transporter from plants identified by functional expression in yeast.
1996,
Pubmed Eng,
Sequence analyses and phylogenetic characterization of the ZIP family of metal ion transport proteins.
1998,
Pubmed Fleming,
Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport.
1998,
Pubmed Forbes,
Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane.
2003,
Pubmed Fukada,
Molecular and genetic features of zinc transporters in physiology and pathogenesis.
2011,
Pubmed Gálvez-Peralta,
ZIP8 zinc transporter: indispensable role for both multiple-organ organogenesis and hematopoiesis in utero.
2012,
Pubmed Gama,
Generation of epitope-tagged proteins by inverse polymerase chain reaction mutagenesis.
2002,
Pubmed Girijashanker,
Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter.
2008,
Pubmed Grass,
The metal permease ZupT from Escherichia coli is a transporter with a broad substrate spectrum.
2005,
Pubmed Grootveld,
Non-transferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterization by high performance liquid chromatography and nuclear magnetic resonance spectroscopy.
1989,
Pubmed Gunshin,
Cloning and characterization of a mammalian proton-coupled metal-ion transporter.
1997,
Pubmed
,
Xenbase Gunshin,
Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver.
2005,
Pubmed He,
ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties.
2006,
Pubmed Heaton,
The use of BeWo cells as an in vitro model for placental iron transport.
2008,
Pubmed Hojyo,
The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth.
2011,
Pubmed Huynh,
A Leishmania amazonensis ZIP family iron transporter is essential for parasite replication within macrophage phagolysosomes.
2006,
Pubmed Illing,
Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1.
2012,
Pubmed
,
Xenbase Järup,
Cadmium overload and toxicity.
2002,
Pubmed Jenkitkasemwong,
Physiologic implications of metal-ion transport by ZIP14 and ZIP8.
2012,
Pubmed Kidane,
Release of iron from ferritin requires lysosomal activity.
2006,
Pubmed Kumfu,
T-type calcium channel as a portal of iron uptake into cardiomyocytes of beta-thalassemic mice.
2011,
Pubmed Lauwerys,
Health risks associated with cobalt exposure--an overview.
1994,
Pubmed Lichten,
Mammalian zinc transporters: nutritional and physiologic regulation.
2009,
Pubmed Liuzzi,
Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells.
2006,
Pubmed Lu,
Transferrin receptor expression in normal, iron-deficient and iron-overloaded rats.
1989,
Pubmed Mackenzie,
Divalent metal-ion transporter DMT1 mediates both H+ -coupled Fe2+ transport and uncoupled fluxes.
2006,
Pubmed
,
Xenbase Mackenzie,
Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1).
2007,
Pubmed
,
Xenbase McArdle,
Role of the placenta in regulation of fetal iron status.
2011,
Pubmed Morgan,
Uptake and subcellular processing of 59Fe-125I-labelled transferrin by rat liver.
1986,
Pubmed Nam,
Effect of dietary iron deficiency and overload on the expression of ZIP metal-ion transporters in rat liver.
2012,
Pubmed Núñez,
Mobilization of iron from endocytic vesicles. The effects of acidification and reduction.
1990,
Pubmed Parkes,
Effects of iron loading on uptake, speciation, and chelation of iron in cultured myocardial cells.
1993,
Pubmed Peters,
Targeting of the mouse Slc39a2 (Zip2) gene reveals highly cell-specific patterns of expression, and unique functions in zinc, iron, and calcium homeostasis.
2007,
Pubmed Pinilla-Tenas,
Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron.
2011,
Pubmed
,
Xenbase Randell,
Uptake of non-transferrin-bound iron by both reductive and nonreductive processes is modulated by intracellular iron.
1994,
Pubmed Richardson,
Activation of an iron uptake mechanism from transferrin in hepatocytes by small-molecular-weight iron complexes: implications for the pathogenesis of iron-overload disease.
1999,
Pubmed Schade,
Interrelationship of cobalt and iron absorption.
1970,
Pubmed Scheiber-Mojdehkar,
Influence of parenteral iron preparations on non-transferrin bound iron uptake, the iron regulatory protein and the expression of ferritin and the divalent metal transporter DMT-1 in HepG2 human hepatoma cells.
2003,
Pubmed Tandy,
Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells.
2000,
Pubmed Taylor,
Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14.
2005,
Pubmed Taylor,
Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters.
2003,
Pubmed Valberg,
Alteration in cobalt absorption in patients with disorders of iron metabolism.
1969,
Pubmed Vayenas,
Influence of iron overload on manganese, zinc, and copper concentration in rat tissues in vivo: study of liver, spleen, and brain.
1998,
Pubmed Versieck,
Trace elements in human body fluids and tissues.
1985,
Pubmed Vert,
Arabidopsis IRT2 gene encodes a root-periphery iron transporter.
2001,
Pubmed Vert,
IRT1, an Arabidopsis transporter essential for iron uptake from the soil and for plant growth.
2002,
Pubmed Wang,
Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter.
2004,
Pubmed Wang,
Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line.
2007,
Pubmed Wang,
The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells.
2004,
Pubmed Zhang,
Hepatic distribution of iron, copper, zinc and cadmium-containing proteins in normal and iron overload mice.
2009,
Pubmed Zhao,
ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin.
2010,
Pubmed
