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.

中文翻译：

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COMMD 蛋白家族成员对铜稳态的调节。

铜是所有真核生物必不可少的过渡金属。在哺乳动物中，肠道铜吸收由 ATP7A 铜转运蛋白介导，而铜排泄主要通过胆道途径发生，并由旁系同源物 ATP7B 介导。两种转运蛋白都被证明可以通过一种称为 COMMD/CCDC22/CCDC93 或 CCC 复合物的分子机制在内体网络和质膜之间积极循环。事实上，COMMD1的突变可导致肝脏特异性Commd1的狗和小鼠的胆汁铜排泄和肝脏病理学受损缺陷也概括了这种表型的各个方面。尽管如此，还没有研究过 CCC 复合物在体内肠道铜吸收中的作用，也没有测试过各种 COMMD 家族成员的潜在冗余。在这项研究中，我们检查了肠细胞特异性和肝细胞特异性Commd 缺陷小鼠的铜稳态。我们发现，与培养细胞系的影响相比，COMMD 蛋白缺乏导致肠细胞中 ATP7A 的变化很小，并且在低铜或高铜饮食下不会导致铜水平改变，这表明肠细胞中 ATP7A 的调节不是生理后果. 相反，缺乏 3 个Commd基因（Commd1、6和9) 在高铜饮食下都会导致肝铜积累。我们发现这些缺陷中的每一个都会导致整个 CCC 复合体的不稳定，并表明这可能解释了它们共有的表型。总体而言，我们得出结论，CCC 复合物在 ATP7B 内体循环和功能中起重要作用。