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Cited by 205Cholesterol and Lipid MetabolismCellular transport and secretionLipoproteins and Cardiovascular Health

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

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Bartuzi, Paulina, Billadeau, Daniel D., Favier, Robert, Rong, Shunxing, Dekker, Daphne, Fedoseienko, Alina, Fieten, Hille, Wijers, Melinde +15 more·2016·Nature Communications
DOI 10.1038/ncomms10961PMC PMC4792963
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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.

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Authors
Bartuzi, P., Billadeau, D. D., Favier, R., Rong, S., Dekker, D., Fedoseienko, A., Fieten, H., Wijers, M., Levels, J. H., Huijkman, N., Kloosterhuis, N., van der Molen, H., Brufau, G., Groen, A. K., Elliott, A. M., Kuivenhoven, J. A., Plecko, B., Grangl, G., McGaughran, J., Horton, J. D., Burstein, E., Hofker, M. H., & van de Sluis, B.
Affiliations
  • University Medical Center Groningen (NL)
  • Mayo Clinic (US)
  • Utrecht University (NL)
  • The University of Texas Southwestern Medical Center (US)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University of British Columbia (CA)
  • Medical University of Graz (AT)
  • The University of Queensland (AU)
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-03-11
Volume
7
Issue
1
Pages
10961-10961
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms10961
PMC
PMC4792963
OpenAlex
W2345206408
Cited by
205
References
3
Citations by year
2026: 8 · 2025: 28 · 2024: 30 · 2023: 20 · 2022: 19 · 2021: 25 · 2020: 21 · 2019: 20 · 2018: 22 · 2017: 9 · 2016: 3
FWCI
17.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (acceptedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Mayo Clinic (P30 DK084567)
  • Jan Kornelis de Cock Stichting
  • European Commission (603091)
  • Rijksuniversiteit Groningen
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (817.02.022)
  • Universitair Medisch Centrum Groningen
  • National Institutes of Health (HL020948)
  • Center for Cell Signaling in Gastroenterology, Mayo Clinic (P30 DK084567)
  • National Heart, Lung, and Blood Institute (HL020948, P01HL020948)
  • National Institute of Allergy and Infectious Diseases (R01AI065474)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK073639, R01DK107733, P30DK084567)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
LDL receptor, endosomal sorting, WASH complex, LDL clearance, hypercholesterolemia, X-linked intellectual disability, COMMD1, lysosomal degradation, cholesterol homeostasis
MeSH terms
Adolescent, Adult, Animals, Child, Child, Preschool, Chromatography, Liquid, Dogs, Female, Fluorescent Antibody Technique, Humans, Hypercholesterolemia, Cholesterol, LDL, Liver, Male, Microfilament Proteins, Middle Aged, Mutation, Proteins, Receptors, LDL, Endosomes, Triglycerides, Mice, Knockout, Protein Transport, Animals, Genetically Modified, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Mice, Young Adult, HEK293 Cells, Transcriptome

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