@article{0354f55ea23141f9b5e4997672cc0eac,
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.",
author = "Paulina Bartuzi and Billadeau, {Daniel D.} and Robert Favier and Shunxing Rong and Daphne Dekker and Alina Fedoseienko and Hille Fieten and Melinde Wijers and Levels, {Johannes H.} and Nicolette Huijkman and Niels Kloosterhuis and {Van Der Molen}, Henk and Gemma Brufau and Groen, {Albert K.} and Elliott, {Alison M.} and Kuivenhoven, {Jan Albert} and Barbara Plecko and Gernot Grangl and Julie McGaughran and Horton, {Jay D.} and Ezra Burstein and Hofker, {Marten H.} and {Van De Sluis}, Bart",
note = "Funding Information: We are grateful to H.H. Hobbs (Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA) for providing the rabbit polyclonal antibody against ARH and to N. Freedman (Department of Medicine, Duke University Medical Center, Durham, NC, USA) for providing the various LDLR expression constructs. We thank S. IJzendoorn (Cell Biology-Membrane Cell Biology, University of Groningen, the Netherlands) for providing Alexa633-transferrin. We thank Sanne Wilbrink for technical assistance, and Laura Damiano for critically reading the manuscript. The work was partly funded by the Groningen University Institute for Drug Exploration (GUIDE; granted to B.v.d.S.), a NWO-ALW grant (817.02.022) to B.v.d.S., a Jan Kornelis de Cock foundation (University Medical Center Groningen) grant to P.B. and B..v.d.S., an EU TransCard (FP7-603091–2) grant to J.A.K./B.v.d.S., NIH grants R01 DK073639 to E.B. and R01 AI065474 to D.D.B, and a NIH grant (HL020948) to J.D.H. This work was supported by the Optical Microscopy Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567).",
year = "2016",
month = mar,
day = "11",
doi = "10.1038/ncomms10961",
language = "English (US)",
volume = "7",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}