title: COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A.
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.
authors.affiliation: Department of Immunology.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Phillips-Krawczak
authors.affiliation: Department of Internal Medicine and.
authors.forename: Amika
authors.initials: A
authors.lastname: Singla
authors.affiliation: Department of Internal Medicine and.
authors.forename: Petro
authors.initials: P
authors.lastname: Starokadomskyy
authors.affiliation: Department of Immunology, Department of Pathophysiology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Immunology.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Osborne
authors.affiliation: Department of Internal Medicine and.
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Immunology.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Dick
authors.affiliation: Department of Immunology.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Gomez
authors.affiliation: Department of Internal Medicine and.
authors.forename: Megan
authors.initials: M
authors.lastname: Koenecke
authors.affiliation: Department of Immunology, School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, and.
authors.forename: Haiming
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Internal Medicine and.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Sifuentes-Dominguez
authors.affiliation: Department of Internal Medicine and.
authors.forename: Linda N
authors.initials: LN
authors.lastname: Geng
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, and.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Marco Y
authors.initials: MY
authors.lastname: Hein
authors.affiliation: Genetic Health Queensland at the Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
authors.forename: Mathew
authors.initials: M
authors.lastname: Wallis
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: McGaughran
authors.affiliation: Robinson Institute and Department of Paediatrics, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Section of Molecular Genetics at the Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9713 Groningen, Netherlands.
authors.forename: Bart van de
authors.initials: Bv
authors.lastname: Sluis
authors.affiliation: Department of Immunology, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905 billadeau.daniel@mayo.edu ezra.burstein@utsouthwestern.edu.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Department of Internal Medicine and Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390-9151 billadeau.daniel@mayo.edu ezra.burstein@utsouthwestern.edu.
authors.forename: Ezra
authors.initials: E
authors.lastname: Burstein
mesh_terms: D008841:Actin Cytoskeleton; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D002465:Cell Movement; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D003593:Cytoplasm / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C571908:CCDC22 protein, human; C480519:COMMD1 protein, human; D027682:Cation Transport Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D011506:Proteins; C476226:VPS35L protein, human; D033921:Vesicular Transport Proteins; C549919:WASH protein, human; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases