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

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

  • Mol Biol Cell. 2015 Jan 1;26(1):91-103. doi: 10.1091/mbc.E14-06-1073.
Christine A Phillips-Krawczak 1,  Amika Singla 2,  Petro Starokadomskyy 2,  Zhihui Deng 3,  Douglas G Osborne 1,  Haiying Li 2,  Christopher J Dick 1,  Timothy S Gomez 1,  Megan Koenecke 2,  Jin-San Zhang 4,  Haiming Dai 5,  Luis F Sifuentes-Dominguez 2,  Linda N Geng 2,  Scott H Kaufmann 5,  Marco Y Hein 6,  Mathew Wallis 7,  Julie McGaughran 8,  Jozef Gecz 9,  Bart van de Sluis 10,  Daniel D Billadeau 11,  Ezra Burstein 12
Affiliations

Affiliations

  • 1 Department of Immunology.
  • 2 Department of Internal Medicine and.
  • 3 Department of Immunology, Department of Pathophysiology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, China.
  • 4 Department of Immunology, School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 5 Department of Molecular Pharmacology and Experimental Therapeutics, and.
  • 6 Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
  • 7 Genetic Health Queensland at the Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
  • 8 Genetic Health Queensland at the Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia School of Medicine, University of Queensland, Brisbane, Queensland 4072, Australia.
  • 9 Robinson Institute and Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5005, Australia.
  • 10 Section of Molecular Genetics at the Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9713 Groningen, Netherlands.
  • 11 Department of Immunology, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905 [email protected] [email protected].
  • 12 Department of Internal Medicine and Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390-9151 [email protected] [email protected].
PMID: 25355947 DOI: 10.1091/mbc.E14-06-1073
Abstract

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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