title: CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL.
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.
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Paulina
authors.initials: P
authors.lastname: Bartuzi
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3584 CM Utrecht, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Favier
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Shunxing
authors.initials: S
authors.lastname: Rong
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: Dekker
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Alina
authors.initials: A
authors.lastname: Fedoseienko
authors.affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3584 CM Utrecht, The Netherlands.
authors.forename: Hille
authors.initials: H
authors.lastname: Fieten
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Melinde
authors.initials: M
authors.lastname: Wijers
authors.affiliation: Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Levels
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Nicolette
authors.initials: N
authors.lastname: Huijkman
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Kloosterhuis
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: van der Molen
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Gemma
authors.initials: G
authors.lastname: Brufau
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Department of Medical Genetics, University of British Columbia, 4500 Oak Street, Vancouver, British Columbia, Canada V6H 3N1.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Elliott
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.affiliation: Department of Pediatrics and Adolescence Medicine, Division of Child Neurology, Medical University Graz, Auenbruggerplatz 2, A-8036 Graz, Austria.|Division of Child Neurology, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.affiliation: Department of Pediatrics and Adolescence Medicine, Division of Child Neurology, Medical University Graz, Auenbruggerplatz 2, A-8036 Graz, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Grangl
authors.affiliation: Genetic Health Queensland at the Royal Brisbane and Women's Hospital, Herston, University of Queensland, Herston, Brisbane, Queensland 4029, Australia.|School of Medicine, University of Queensland, Herston, Brisbane, Queensland 4029, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: McGaughran
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.|Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Ezra
authors.initials: E
authors.lastname: Burstein
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D002648:Child; D002675:Child, Preschool; D008078:Cholesterol, LDL / Q000378:metabolism*; D002853:Chromatography, Liquid; D004285:Dogs; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D047468:Immunoprecipitation; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D011973:Receptors, LDL / Q000378:metabolism*; D059467:Transcriptome; D014280:Triglycerides / Q000378:metabolism*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C571908:CCDC22 protein, human; D008078:Cholesterol, LDL; C103799:Commd1 protein, mouse; C000609356:Commd9 protein, mouse; D008840:Microfilament Proteins; D011506:Proteins; D011973:Receptors, LDL; D014280:Triglycerides; C549919:WASH protein, human; C517003:WASHC5 protein, human