Abstract
ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively 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 in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. 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 gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused 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.
Highlights
COMMD protein deficiency destabilizes the CCC complex in enterocytes and hepatocytes Previously, using cell culture models, we have shown that the CCC complex regulates endosomal trafficking of the copper transporter, ATP7A (Phillips-Krawczak et al, 2015), the key copper transporter involved in intestinal absorption of copper (Wang et al, 2011)
Deficiency of COMMD1 or COMMD9 resulted in the depletion of core components of the CCC complex (CCDC22 and CCDC93), in addition to VPS35L (Fig. 1A), a subunit shared by the CCC and retriever complexes (Singla et al, 2019)
COMMD proteins are highly conserved factors that have been linked to various physiological functions, including copper homeostasis (Phillips-Krawczak et al, 2015; van de Sluis et al, 2002; Vonk et al, 2011), inflammation (Li et al, 2014; Maine et al, 2007; Starokadomskyy et al, 2013), lipid metabolism (Bartuzi et al, 2016; Fedoseienko et al, 2018), adaptation to hypoxia and electrolyte transport (Biasio et al, 2004; Drévillon et al, 2011; Ware et al, 2018)
Summary
Copper is an essential trace element that is required for the activity of various conserved enzymes that catalyze oxygen-dependent. Owing to its oxidative activity, excess copper is toxic to biological systems and, as a result, intracellular levels of copper are tightly regulated (Rae et al, 1999). In this regard, movement of copper across membranes is regulated carefully by the P-type ATPase transporters, ATP7A and ATP7B (Puig et al, 2002; Wang et al, 2011). ATP7A is expressed in most tissues, including the intestine, where it is required for intestinal copper absorption, whereas ATP7B is expressed predominantly in the liver, where it is required for biliary copper excretion, the physiological route of copper elimination
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