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. HortonEzra Burstein, Marten H. Hofker, Bart Van De Sluis

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

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.

Original languageEnglish (US)
Article number10961
JournalNature communications
Volume7
DOIs
StatePublished - Mar 11 2016

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

Fingerprint

Dive into the research topics of 'CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL'. Together they form a unique fingerprint.

Cite this