Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron

Jorge J. Pinilla-Tenas, Brian K. Sparkman, Ali Shawki, Anthony C. Illing, Colin J. Mitchell, Ningning Zhao, Juan P. Liuzzi, Robert J. Cousins, Mitchell D. Knutson, Bryan Mackenzie

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume301
Issue number4
DOIs
StatePublished - Oct 2011
Externally publishedYes

Fingerprint

Zinc
Iron
Metals
Ions
Proteins
Oocytes
Nitrilotriacetic Acid
Iron Overload
Xenopus laevis
Protein Transport
Hepatocytes
Temperature
Liver

Keywords

  • Cadmium transport
  • Hereditary hemochromatosis
  • Homeostasis iron transport
  • Iron
  • SLC39A14
  • Thalassemia
  • Xenopus laevis oocyte
  • Zinc transport

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

Cite this

Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. / Pinilla-Tenas, Jorge J.; Sparkman, Brian K.; Shawki, Ali; Illing, Anthony C.; Mitchell, Colin J.; Zhao, Ningning; Liuzzi, Juan P.; Cousins, Robert J.; Knutson, Mitchell D.; Mackenzie, Bryan.

In: American Journal of Physiology - Cell Physiology, Vol. 301, No. 4, 10.2011.

Research output: Contribution to journalArticle

Pinilla-Tenas, Jorge J. ; Sparkman, Brian K. ; Shawki, Ali ; Illing, Anthony C. ; Mitchell, Colin J. ; Zhao, Ningning ; Liuzzi, Juan P. ; Cousins, Robert J. ; Knutson, Mitchell D. ; Mackenzie, Bryan. / Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. In: American Journal of Physiology - Cell Physiology. 2011 ; Vol. 301, No. 4.
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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

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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.

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