COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A

COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex...

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Bibliographic Details
Published in:Molecular biology of the cell 2015-01, Vol.26 (1), p.91-103
Main Authors: Phillips-Krawczak, Christine A, Singla, Amika, Starokadomskyy, Petro, Deng, Zhihui, Osborne, Douglas G, Li, Haiying, Dick, Christopher J, Gomez, Timothy S, Koenecke, Megan, Zhang, Jin-San, Dai, Haiming, Sifuentes-Dominguez, Luis F, Geng, Linda N, Kaufmann, Scott H, Hein, Marco Y, Wallis, Mathew, McGaughran, Julie, Gecz, Jozef, Sluis, Bart van de, Billadeau, Daniel D, Burstein, Ezra
Format: Article
Language:English
Subjects:
Actin Cytoskeleton
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Adenosine Triphosphatases - metabolism
Animals
Cation Transport Proteins - metabolism
Cell Movement
Copper - metabolism
Copper-Transporting ATPases
Cytoplasm - metabolism
Endosomes - metabolism
HEK293 Cells
HeLa Cells
Homeostasis
Humans
Mice
Microfilament Proteins - metabolism
Mutation
Neoplasm Proteins - metabolism
Proteins - genetics
Proteins - metabolism
Transport Vesicles - metabolism
Vesicular Transport Proteins
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Summary:COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.e14-06-1073