Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite uptake

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.