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Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B.
J Biol Chem. 2012 Jan 20; 287(4):2485-99.JB

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+Show Affiliations

Strategic Research Centre for Molecular and Medical Research, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22130675

Citation

Materia, Stephanie, et al. "Clusterin and COMMD1 Independently Regulate Degradation of the Mammalian Copper ATPases ATP7A and ATP7B." The Journal of Biological Chemistry, vol. 287, no. 4, 2012, pp. 2485-99.
Materia S, Cater MA, Klomp LW, et al. Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. J Biol Chem. 2012;287(4):2485-99.
Materia, S., Cater, M. A., Klomp, L. W., Mercer, J. F., & La Fontaine, S. (2012). Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. The Journal of Biological Chemistry, 287(4), 2485-99. https://doi.org/10.1074/jbc.M111.302216
Materia S, et al. Clusterin and COMMD1 Independently Regulate Degradation of the Mammalian Copper ATPases ATP7A and ATP7B. J Biol Chem. 2012 Jan 20;287(4):2485-99. PubMed PMID: 22130675.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. AU - Materia,Stephanie, AU - Cater,Michael A, AU - Klomp,Leo W J, AU - Mercer,Julian F B, AU - La Fontaine,Sharon, Y1 - 2011/11/30/ PY - 2011/12/2/entrez PY - 2011/12/2/pubmed PY - 2012/3/16/medline SP - 2485 EP - 99 JF - The Journal of biological chemistry JO - J Biol Chem VL - 287 IS - 4 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/22130675/Clusterin_and_COMMD1_independently_regulate_degradation_of_the_mammalian_copper_ATPases_ATP7A_and_ATP7B_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)53210-9 DB - PRIME DP - Unbound Medicine ER -