Regulation of murine copper homeostasis by members of the COMMD protein family
| Autor: | Jie Song, Adam M. Lopez, Kohei Suzuki, Bart van de Sluis, Qing Chen, Alina Fedoseienko, Melinde Wijers, Daniel D. Billadeau, Ezra Burstein, Amika Singla |
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| Přispěvatelé: | Center for Liver, Digestive and Metabolic Diseases (CLDM), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE) |
| Rok vydání: | 2021 |
| Předmět: |
Protein family
atp7b Endosome atp7a ATP7A Neuroscience (miscellaneous) lcsh:Medicine Medicine (miscellaneous) chemistry.chemical_element Endosomes General Biochemistry Genetics and Molecular Biology commd proteins Mice Immunology and Microbiology (miscellaneous) Cell Line Tumor lcsh:Pathology Animals Homeostasis Humans Gene Adaptor Proteins Signal Transducing Mice Knockout Chemistry lcsh:R Ceruloplasmin copper homeostasis Transporter copper transporters Copper Phenotype Cell biology Enterocytes Gene Expression Regulation endosomal trafficking Copper-Transporting ATPases Mutation Hepatocytes Function (biology) Research Article lcsh:RB1-214 |
| Zdroj: | Disease Models & Mechanisms, Vol 14, Iss 1 (2021) Disease Models & Mechanisms article-version (VoR) Version of Record Disease models & mechanisms, 14. COMPANY OF BIOLOGISTS LTD |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.045963 |
| Popis: | 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 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. Summary: Examination of copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice revealed that homologs of COMMD1, which has been linked previously by genetic studies to copper regulation, also regulate copper handling in mammals. |
| Databáze: | OpenAIRE |
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