CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL

Paulina Bartuzi, Daniel D. Billadeau, Robert Favier, Shunxing Rong, Daphne Dekker, Alina Fedoseienko, Hille Fieten, Melinde Wijers, Johannes H. Levels, Nicolette Huijkman, Niels Kloosterhuis, Henk van der Molen, Gemma Brufau, Albert K. Groen, Alison M. Elliott, Jan Albert Kuivenhoven, Barbara Plecko, Gernot Grangl, Julie McGaughran, Jay D. Horton, Ezra Burstein, Marten H. Hofker and Bart van de Sluis ()
Additional contact information
Paulina Bartuzi: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Daniel D. Billadeau: Mayo Clinic College of Medicine, Mayo Clinic
Robert Favier: Faculty of Veterinary Medicine, Utrecht University
Shunxing Rong: University of Texas Southwestern Medical Center
Daphne Dekker: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Alina Fedoseienko: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Hille Fieten: Faculty of Veterinary Medicine, Utrecht University
Melinde Wijers: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Johannes H. Levels: Academic Medical Center, University of Amsterdam
Nicolette Huijkman: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Niels Kloosterhuis: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Henk van der Molen: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Gemma Brufau: University of Groningen, University Medical Center Groningen
Albert K. Groen: University of Groningen, University Medical Center Groningen
Alison M. Elliott: University of British Columbia
Jan Albert Kuivenhoven: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Barbara Plecko: Medical University Graz
Gernot Grangl: Medical University Graz
Julie McGaughran: Genetic Health Queensland at the Royal Brisbane and Women’s Hospital, Herston, University of Queensland
Jay D. Horton: University of Texas Southwestern Medical Center
Ezra Burstein: University of Texas Southwestern Medical Center
Marten H. Hofker: Molecular Genetics Section, University of Groningen, University Medical Center Groningen
Bart van de Sluis: Molecular Genetics Section, University of Groningen, University Medical Center Groningen

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms10961

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