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

Bartuzi, Paulina, Billadeau, Daniel D., Favier, Robert, Rong, Shunxing, Dekker, Daphne, Fedoseienko, Alina, Fieten, Hille, Wijers, Melinde, Levels, Johannes H., Huijkman, Nicolette, Kloosterhuis, Niels, Van Der Molen, Henk, Brufau, Gemma, Groen, Albert K., Elliott, Alison M., Kuivenhoven, Jan Albert, Plecko, Barbara, Grangl, Gernot, McGaughran, Julie, Horton, Jay D., Burstein, Ezra, Hofker, Marten H. and Van De Sluis, Bart (2016) CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nature Communications, 7 . doi:10.1038/ncomms10961


Author Bartuzi, Paulina
Billadeau, Daniel D.
Favier, Robert
Rong, Shunxing
Dekker, Daphne
Fedoseienko, Alina
Fieten, Hille
Wijers, Melinde
Levels, Johannes H.
Huijkman, Nicolette
Kloosterhuis, Niels
Van Der Molen, Henk
Brufau, Gemma
Groen, Albert K.
Elliott, Alison M.
Kuivenhoven, Jan Albert
Plecko, Barbara
Grangl, Gernot
McGaughran, Julie
Horton, Jay D.
Burstein, Ezra
Hofker, Marten H.
Van De Sluis, Bart
Title CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2016-03-11
Year available 2016
Sub-type Article (original research)
DOI 10.1038/ncomms10961
Open Access Status DOI
Volume 7
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1600 Chemistry
1300 Biochemistry, Genetics and Molecular Biology
3100 Physics and Astronomy
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.
Formatted 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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 817.02.022
FP7-603091-2
R01 DK073639
P30DK084567
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
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