title: Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B.
abstract: ATP7A and ATP7B are copper-transporting P(1B)-type ATPases (Cu-ATPases) that are critical for regulating intracellular copper homeostasis. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and copper toxicity disorders, Menkes and Wilson diseases, respectively. Clusterin and COMMD1 were previously identified as interacting partners of these Cu-ATPases. In this study, we confirmed that clusterin and COMMD1 interact to down-regulate both ATP7A and ATP7B. Overexpression and knockdown of clusterin/COMMD1 decreased and increased, respectively, endogenous levels of ATP7A and ATP7B, consistent with a role in facilitating Cu-ATPase degradation. We demonstrate that whereas the clusterin/ATP7B interaction was enhanced by oxidative stress or mutation of ATP7B, the COMMD1/ATP7B interaction did not change under oxidative stress conditions, and only increased with ATP7B mutations that led to its misfolding. Clusterin and COMMD1 facilitated the degradation of ATP7B containing the same Wilson disease-causing C-terminal mutations via different degradation pathways, clusterin via the lysosomal pathway and COMMD1 via the proteasomal pathway. Furthermore, endogenous ATP7B existed in a complex with clusterin and COMMD1, but these interactions were neither competitive nor cooperative and occurred independently of each other. Together these data indicate that clusterin and COMMD1 represent alternative and independent systems regulating Cu-ATPase quality control, and consequently contributing to the maintenance of copper homeostasis.
authors: Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors: Stephanie
authors: S
authors: Materia
authors: Michael A
authors: MA
authors: Cater
authors: Leo W J
authors: LW
authors: Klomp
authors: Julian F B
authors: JF
authors: Mercer
authors: Sharon
authors: S
authors: La Fontaine
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; 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*; D000073840:Copper-Transporting ATPases; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D059748:Proteolysis; D051381:Rats
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486201:Atp7a protein, mouse; C495242:CLU protein, human; C480519:COMMD1 protein, human; C549962:COMMD1 protein, rat; D027682:Cation Transport Proteins; C495243:Clu protein, mouse; C498500:Clu protein, rat; D051152:Clusterin; C103799:Commd1 protein, mouse; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; C486202:Atp7a protein, rat; C550619:Atp7b protein, rat; D000073840:Copper-Transporting ATPases