TY - JOUR
T1 - Functional partnership of the copper export machinery and glutathione balance in human cells
AU - Hatori, Yuta
AU - Clasen, Sara
AU - Hasan, Nesrin M.
AU - Barry, Amanda N.
AU - Lutsenko, Svetlana
PY - 2012/8/3
Y1 - 2012/8/3
N2 - Cells use the redox properties of copper in numerous physiologic processes, including antioxidant defense, neurotransmitter biosynthesis, and angiogenesis. Copper delivery to the secretory pathway is an essential step in copper utilization and homeostatic maintenance. We demonstrate that the glutathione/ glutathione disulfide (GSH/GSSG) pair controls the copper transport pathway by regulating the redox state of a copper chaperone Atox1.GSSGoxidizes copper-coordinating cysteines of Atox1 with the formation of an intramolecular disulfide.GSH alone is sufficient to reduce the disulfide, restoring the ability of Atox1 to bind copper; glutaredoxin 1 facilitates this reaction when GSH is low. In cells, high GSH both reduces Atox1 and is required for cell viability in the absence of Atox1. In turn, Atox1, which has a redox potential similar to that of glutaredoxin, becomes essential for cell survival when GSH levels decrease. Atox1+/+ cells resist short term glutathione depletion, whereas Atox1-/- cells under the same conditions are not viable. We conclude that GSH balance and copper homeostasis are functionally linked and jointly maintain conditions for copper secretion and cell proliferation.
AB - Cells use the redox properties of copper in numerous physiologic processes, including antioxidant defense, neurotransmitter biosynthesis, and angiogenesis. Copper delivery to the secretory pathway is an essential step in copper utilization and homeostatic maintenance. We demonstrate that the glutathione/ glutathione disulfide (GSH/GSSG) pair controls the copper transport pathway by regulating the redox state of a copper chaperone Atox1.GSSGoxidizes copper-coordinating cysteines of Atox1 with the formation of an intramolecular disulfide.GSH alone is sufficient to reduce the disulfide, restoring the ability of Atox1 to bind copper; glutaredoxin 1 facilitates this reaction when GSH is low. In cells, high GSH both reduces Atox1 and is required for cell viability in the absence of Atox1. In turn, Atox1, which has a redox potential similar to that of glutaredoxin, becomes essential for cell survival when GSH levels decrease. Atox1+/+ cells resist short term glutathione depletion, whereas Atox1-/- cells under the same conditions are not viable. We conclude that GSH balance and copper homeostasis are functionally linked and jointly maintain conditions for copper secretion and cell proliferation.
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U2 - 10.1074/jbc.M112.381178
DO - 10.1074/jbc.M112.381178
M3 - Article
C2 - 22648419
AN - SCOPUS:84864554815
SN - 0021-9258
VL - 287
SP - 26678
EP - 26687
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 32
ER -