Clusterin (apolipoprotein J), a molecular chaperone that facilitates degradation of the copper-ATPases ATP7A and ATP7B.
The copper-transporting P(1B)-type ATPases (Cu-ATPases) ATP7A and ATP7B are key regulators of physiological copper levels. They function to maintain intracellular copper homeostasis by delivering copper to secretory compartments and by trafficking toward the cell periphery to export excess copper. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and toxicity disorders, Menkes and Wilson diseases, respectively. This report describes the interaction between the Cu-ATPases and clusterin and demonstrates a chaperone-like role for clusterin in facilitating their degradation. Clusterin interacted with both ATP7A and ATP7B in mammalian cells. This interaction increased under conditions of oxidative stress and with mutations in ATP7B that led to its misfolding and mislocalization. A Wilson disease patient mutation (G85V) led to enhanced ATP7B turnover, which was further exacerbated when cells overexpressed clusterin. We demonstrated that clusterin-facilitated degradation of mutant ATP7B is likely to involve the lysosomal pathway. The knockdown and overexpression of clusterin increased and decreased, respectively, the Cu-ATPase-mediated copper export capacity of cells. These results highlight a new role for intracellular clusterin in mediating Cu-ATPase quality control and hence in the normal maintenance of copper homeostasis, and in promoting cell survival in the context of disease. Based on our findings, it is possible that variations in clusterin expression and function could contribute to the variable clinical expression of Menkes and Wilson diseases.
Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.
Stephanie
S
Materia
Michael A
MA
Cater
Leo W J
LW
Klomp
Julian F B
JF
Mercer
Sharon
S
La Fontaine
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding
C495242:CLU protein, human; D027682:Cation Transport Proteins; D051152:Clusterin; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases
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