Bartuzi Paulina, Billadeau Daniel D, Favier Robert, Rong Shunxing, Dekker Daphne, Fedoseienko Alina, Fieten Hille, Wijers Melinde, Levels Johannes H, Huijkman Nicolette, Kloosterhuis Niels, van der Molen Henk, Brufau Gemma, Groen Albert K, Elliott Alison M, Kuivenhoven Jan Albert, Plecko Barbara, Grangl Gernot, McGaughran Julie, Horton Jay D, Burstein Ezra, Hofker Marten H, van de Sluis Bart
Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA.
Nat Commun. 2016 Mar 11;7:10961. doi: 10.1038/ncomms10961.
The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.
低密度脂蛋白受体（LDLR）在清除致动脉粥样硬化的循环低密度脂蛋白（LDL）胆固醇方面发挥着关键作用。在此，我们表明COMMD/CCDC22/CCDC93（CCC）复合物和威斯科特-奥尔德里奇综合征蛋白及SCAR同源物（WASH）复合物对于LDLR的内体分选及其功能均至关重要。我们发现，由CCDC22突变导致的X连锁智力障碍患者存在高胆固醇血症，并且COMMD1缺陷犬和肝脏特异性Commd1基因敲除小鼠的血浆LDL胆固醇水平升高。此外，Commd1缺失导致LDLR定位错误，同时LDL摄取减少。肝脏COMMD9缺陷小鼠的血浆总胆固醇水平也升高。与CCC相关的WASH复合物失活会导致LDLR定位错误、LDLR的溶酶体降解增加以及LDL摄取受损。此外，WASH组分KIAA0196（斯特伦佩林）的突变与人类高胆固醇血症相关。总之，本研究为调节胆固醇稳态和LDLR转运的机制提供了有价值的见解。
