Regulation of murine copper homeostasis by members of the COMMD protein family

Abstract

Copper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominatly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be actively recycled between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and mice with liver-specific Commd1 deficiency recapitulating aspects of this phenotype as well. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific Commd-deficient mice. We find that in contrast to effects in cell lines in culture, COMMD protein deficiency induces minimal changes in ATP7A in enterocytes and does not lead to altered copper levels under low or high copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiologic consequence. In contrast, deficiency of any of 3 Commd genes (Commd1, 6, and 9) all result in hepatic copper accumulation under high copper diets. We find that each of these deficiencies cause destabilization of the entire CCC complex, and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.

Crossroads between membrane trafficking machinery and copper homeostasis in the nerve system

“…COMMD1, by far, is the only identified membrane trafficking regulator with Cu-binding capability that directly mediates cellular Cu homeostasis [ 106 , 179 , 180 ]. Recent studies in tissue-specific knockout mice suggested that, within the COMMD family, Commd6 and Commd9 might also play a similar role as Commd1, since mice with liver-specific deficiency on Commd1, Commd6 or Commd9 shared the same Cu accumulation phenotype in the liver [ 235 ]. Further, COMMD1 has been reported to regulate the trafficking of ATP7A and ATP7B, whose functions and distributions are similar but not identical [ 86 ].…”

“…Current molecular understanding of Cu transporters trafficking is mainly originated from non-neuronal cells. This could be a concern since Cu homeostasis and the trafficking of Atp7a show drastic differences between mice intestine and liver cells [ 235 ]. This observation suggests potential differences in the trafficking of neurons and non-neuronal cells that were primarily neglected in the past.…”

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“…In contrast, intestinal deletion of COMMD1 (and COMMD9) did not show altered Cu levels in enterocytes. Moreover, these animals did not show reduced serum ceruloplasmin levels when fed ammonia tetrathiomolybdate, a specific Cu chelator that induces Cu deficiency in animals, demonstrating organ-specificity of COMMD's functions [50].…”

“…COMMD1 is also required for ATP7B trafficking [52]. Hepatic deletions of COMMD1 results in accumulation of Cu and development of Cu toxicosis in the livers [50,53]. In contrast, intestinal deletion of COMMD1 (and COMMD9) did not show altered Cu levels in enterocytes.…”

“…Under low Cu conditions, ATP7A and ATP7B are mainly associated with TGN [44]; whereas under elevated Cu conditions, they move via endosomal vesicle to peripheral membrane where Cu(I) is exported out of the cells. Both ATP7A and ATP7B actively recycle between the endosomal network and the plasma membrane by a molecular machinery called the CCD complex (COMMD/CCDC22/CCDC93) [50]. This complex consists of COMMD1 (the copper metabolism MURR1 domain 1) and coil-coil proteins CCDC22 and CCDC93.…”