TY - JOUR
T1 - Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron
AU - Pinilla-Tenas, Jorge J.
AU - Sparkman, Brian K.
AU - Shawki, Ali
AU - Illing, Anthony C.
AU - Mitchell, Colin J.
AU - Zhao, Ningning
AU - Liuzzi, Juan P.
AU - Cousins, Robert J.
AU - Knutson, Mitchell D.
AU - Mackenzie, Bryan
PY - 2011/10
Y1 - 2011/10
N2 - Recent studies have shown that overexpression of the transmembrane protein Zrt-and Irt-like protein 14 (Zip14) stimulates the cellular uptake of zinc and nontransferrin-bound iron (NTBI). Here, we directly tested the hypothesis that Zip14 transports free zinc, iron, and other metal ions by using the Xenopus laevis oocyte heterologous expression system, and use of this approach also allowed us to characterize the functional properties of Zip14. Expression of mouse Zip14 in RNAinjected oocytes stimulated the uptake of 55Fe in the presence of L-ascorbate but not nitrilotriacetic acid, indicating that Zip14 is an iron transporter specific for ferrous ion (Fe 2+) over ferric ion ( Fe3+). Zip14-mediated 55Fe 2+ uptake was saturable (K 0.5 ≈ 2 μM), temperature-dependent (apparent activation energy, E a = 15 kcal/mol), pH-sensitive, Ca 2+-dependent, and inhibited by Co 2+, Mn 2+, and Zn 2+. HCO 3 - + stimulated 55Fe 2+ transport. These properties are in close agreement with those of NTBI uptake in the perfused rat liver and in isolated hepatocytes reported in the literature. Zip14 also mediated the uptake of 109Cd 2+, 54Mn 2+, and 65Zn 2+ but not 64Cu (I or II). 65Zn 2+ uptake also was saturable (K0.5 ≈ 2μM) but, notably, the metal-ion inhibition profile and Ca 2+ dependence of Zn 2+ transport differed from those of Fe 2+ transport, and we propose a model to account for these observations. Our data reveal that Zip14 is a complex, broad-scope metal-ion transporter. Whereas zinc appears to be a preferred substrate under normal conditions, we found that Zip14 is capable of mediating cellular uptake of NTBI characteristic of iron-overload conditions.
AB - Recent studies have shown that overexpression of the transmembrane protein Zrt-and Irt-like protein 14 (Zip14) stimulates the cellular uptake of zinc and nontransferrin-bound iron (NTBI). Here, we directly tested the hypothesis that Zip14 transports free zinc, iron, and other metal ions by using the Xenopus laevis oocyte heterologous expression system, and use of this approach also allowed us to characterize the functional properties of Zip14. Expression of mouse Zip14 in RNAinjected oocytes stimulated the uptake of 55Fe in the presence of L-ascorbate but not nitrilotriacetic acid, indicating that Zip14 is an iron transporter specific for ferrous ion (Fe 2+) over ferric ion ( Fe3+). Zip14-mediated 55Fe 2+ uptake was saturable (K 0.5 ≈ 2 μM), temperature-dependent (apparent activation energy, E a = 15 kcal/mol), pH-sensitive, Ca 2+-dependent, and inhibited by Co 2+, Mn 2+, and Zn 2+. HCO 3 - + stimulated 55Fe 2+ transport. These properties are in close agreement with those of NTBI uptake in the perfused rat liver and in isolated hepatocytes reported in the literature. Zip14 also mediated the uptake of 109Cd 2+, 54Mn 2+, and 65Zn 2+ but not 64Cu (I or II). 65Zn 2+ uptake also was saturable (K0.5 ≈ 2μM) but, notably, the metal-ion inhibition profile and Ca 2+ dependence of Zn 2+ transport differed from those of Fe 2+ transport, and we propose a model to account for these observations. Our data reveal that Zip14 is a complex, broad-scope metal-ion transporter. Whereas zinc appears to be a preferred substrate under normal conditions, we found that Zip14 is capable of mediating cellular uptake of NTBI characteristic of iron-overload conditions.
KW - Cadmium transport
KW - Hereditary hemochromatosis
KW - Homeostasis iron transport
KW - Iron
KW - SLC39A14
KW - Thalassemia
KW - Xenopus laevis oocyte
KW - Zinc transport
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UR - http://www.scopus.com/inward/citedby.url?scp=80053210392&partnerID=8YFLogxK
U2 - 10.1152/ajpcell.00479.2010
DO - 10.1152/ajpcell.00479.2010
M3 - Article
C2 - 21653899
AN - SCOPUS:80053210392
SN - 0363-6143
VL - 301
SP - C862-C871
JO - American Journal of Physiology
JF - American Journal of Physiology
IS - 4
ER -