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Free keywords:
ALDRICH SYNDROME PROTEIN, WILSON-DISEASE PROTEIN, TOXICOSIS GENE MURR1,
DOMAIN-CONTAINING 1, ARP2/3 ACTIVATOR, UBIQUITIN LIGASE, CELL-LINE,
RETROMER, METABOLISM, INTERACTSCell Biology; Developmental Biology;
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.
