Oncotarget

Research Papers:

Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite uptake

Joseph R. McDermott _, Xiangrong Geng, Lan Jiang, Marina Gálvez-Peralta, Fei Chen, Daniel W. Nebert and Zijuan Liu

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Oncotarget. 2016; 7:35327-35340. https://doi.org/10.18632/oncotarget.9205

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Abstract

Joseph R. McDermott1, Xiangrong Geng1, Lan Jiang1, Marina Gálvez-Peralta2, Fei Chen3, Daniel W. Nebert2, Zijuan Liu1

1Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA

2Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA

3Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA

Correspondence to:

Daniel W. Nebert, email: dan.nebert@uc.edu

Zijuan Liu, email: liu2345@oakland.edu

Keywords: selenite, zinc, micronutrient, ZIP8, membrane-bound transporter

Received: December 26, 2015    Accepted: April 11, 2016    Published: May 6, 2016

ABSTRACT

Selenite (HSeO3) is a monovalent anion of the essential trace element and micronutrient selenium (Se). In therapeutic concentrations, HSeO3 has been studied for treating certain cancers, serious inflammatory disorders, and septic shock. Little is known, however, about HSeO3 uptake into mammalian cells; until now, no mammalian HSeO3 uptake transporter has been identified. The ubiquitous mammalian ZIP8 divalent cation transporter (encoded by the SLC39A8 gene) is bicarbonate-dependent, moving endogenous substrates (Zn2+, Mn2+, Fe2+ or Co2+) and nonessential metals such as Cd2+ into the cell. Herein we studied HSeO3 uptake in: human and mouse cell cultures, shRNA-knockdown experiments, Xenopus oocytes, wild-type mice and two transgenic mouse lines having genetically altered ZIP8 expression, and mouse erythrocytes ex vivo. In mammalian cell culture, excess Zn2+ levels and/or ZIP8 over-expression can be associated with diminished viability in selenite-treated cells. Intraperitoneal HSeO3 causes the largest ZIP8-dependent increases in intracellular Se content in liver, followed by kidney, heart, lung and spleen. In every model system studied, HSeO3 uptake is tightly associated with ZIP8 protein levels and sufficient Zn2+ and HCO3 concentrations, suggesting that the ZIP8-mediated electroneutral complex transported contains three ions: Zn2+/(HCO3)(HSeO3). Transporters having three different ions in their transport complex are not without precedent. Although there might be other HSeO3 influx transporters as yet undiscovered, data herein suggest that mammalian ZIP8 plays a major role in HSeO3 uptake.


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