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

Mol Biol Cell 2015 Jan 29;26(1):91-103. Epub 2014 Oct 29.

Department of Internal Medicine and Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390-9151

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.

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http://dx.doi.org/10.1091/mbc.E14-06-1073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279232PMC
January 2015
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