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

Nat Commun. 2016 Mar 11;7:10961. doi: 10.1038/ncomms10961.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Animals
  • Animals, Genetically Modified
  • Child
  • Child, Preschool
  • Cholesterol, LDL / metabolism*
  • Chromatography, Liquid
  • Dogs
  • Endosomes / metabolism*
  • Female
  • Fluorescent Antibody Technique
  • HEK293 Cells
  • Humans
  • Hypercholesterolemia / genetics*
  • Immunoprecipitation
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / genetics*
  • Middle Aged
  • Mutation
  • Protein Transport / genetics
  • Proteins / genetics*
  • Receptors, LDL / metabolism*
  • Transcriptome
  • Triglycerides / metabolism*
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • CCDC22 protein, human
  • Cholesterol, LDL
  • Commd1 protein, mouse
  • Commd9 protein, mouse
  • Microfilament Proteins
  • Proteins
  • Receptors, LDL
  • Triglycerides
  • WASH protein, human
  • WASHC5 protein, human