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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
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,
Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver.
2005,
Pubmed
Gunshin,
Cloning and characterization of a mammalian proton-coupled metal-ion transporter.
1997,
Pubmed
,
Xenbase
Gálvez-Peralta,
ZIP8 zinc transporter: indispensable role for both multiple-organ organogenesis and hematopoiesis in utero.
2012,
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
Jenkitkasemwong,
Physiologic implications of metal-ion transport by ZIP14 and ZIP8.
2012,
Pubmed
Järup,
Cadmium overload and toxicity.
2002,
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,
IRT1, an Arabidopsis transporter essential for iron uptake from the soil and for plant growth.
2002,
Pubmed
Vert,
Arabidopsis IRT2 gene encodes a root-periphery iron transporter.
2001,
Pubmed
Wang,
The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells.
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,
Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter.
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
