COpper Metabolism MURR1 Domain-containing (COMMD) proteins are a part of the COMMD-CCDC22-CCDC93 (CCC) complexes facilitating endosomal trafficking of cell surface receptors. Hepatic COMMD1 inactivation decreases CCDC22 and CCDC93 protein levels, impairs the recycling of the low-density lipoprotein receptor (LDLR), and increases plasma LDL cholesterol levels in mice. However, whether any of the other COMMD members function similarly as COMMD1, and whether perturbation in the CCC complex promotes atherogenesis remain unclear.
To unravel the contribution of evolutionarily conserved COMMD proteins to plasma lipoprotein levels and atherogenesis.
Methods and Results:
Using liver specific Commd1, Commd6 or Commd9 knockout mice we investigated the relation between the COMMD proteins in the regulation of plasma cholesterol levels. Combining biochemical and quantitative targeted proteomic approaches, we found that either hepatic COMMD1, COMMD6 or COMMD9 deficiency resulted in massive reduction in the protein levels of all ten COMMDs. This decrease in COMMD proteins levels coincided with destabilizing of the core (CCDC22, CCDC93, C16orf62) of the CCC complex, reduced cell surface levels of LDLR and LRP1, followed by increased plasma LDL cholesterol levels. To assess the direct contribution of the CCC core in the regulation of plasma cholesterol levels, Ccdc22 was deleted in mouse livers via CRISPR/Cas9-mediated somatic gene editing. CCDC22 deficiency also destabilized the complete CCC complex, and resulted in elevated plasma LDL cholesterol levels. Finally, we found that hepatic disruption of the CCC complex exacerbates dyslipidemia and atherosclerosis in ApoE3*Leiden mice.
Collectively, these findings demonstrate a strong interrelationship between COMMD proteins and the core of the CCC complex in endosomal LDLR trafficking. Hepatic disruption of either of these CCC components causes hypercholesterolemia, and exacerbates atherosclerosis. Our results indicate that not only COMMD1, but all other COMMDs and CCC components may be potential targets for modulating plasma lipid levels in humans.
Alina Fedoseienko, Melinde Wijers, Justina C Wolters, Daphne Dekker, Marieke Smit, Nicolette Huijkman, Niels Kloosterhuis, Helene Klug, Aloys Schepers, Ko Willems van Dijk, Johannes H Levels, Daniel D Billadeau, Marten H Hofker, Jan van Deursen, Marit Westerterp, Ezra Burstein, Jan Albert Kuivenhoven and Bart van de Sluis
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