Functional partnership of the copper export machinery and glutathione balance in human cells.
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. GSSG oxidizes 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.
Department of Physiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Yuta
Y
Hatori
Sara
S
Clasen
Nesrin M
NM
Hasan
Amanda N
AN
Barry
Svetlana
S
Lutsenko
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D000073840:Copper-Transporting ATPases; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D056511:Metallochaperones; D018832:Molecular Chaperones / Q000737:chemistry / Q000502:physiology*; D010084:Oxidation-Reduction
C474500:ATOX1 protein, human; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D003300:Copper; D005980:Glutathione Reductase; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D005978:Glutathione