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 journalArticle

42 Citations (Scopus)

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

Fingerprint

Wiskott-Aldrich Syndrome Protein
lipoproteins
LDL Receptors
clearances
classifying
LDL Lipoproteins
Sorting
proteins
cholesterol
LDL Cholesterol
Cholesterol
Plasmas
mutations
Mutation
Liver
Hypercholesterolemia
Knockout Mice
Intellectual Disability
knockout mice
disabilities

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Bartuzi, P., Billadeau, D. D., Favier, R., Rong, S., Dekker, D., Fedoseienko, A., ... Van De Sluis, B. (2016). CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nature Communications, 7, [10961]. https://doi.org/10.1038/ncomms10961

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.; Van De Sluis, Bart.

In: Nature Communications, Vol. 7, 10961, 11.03.2016.

Research output: Contribution to journalArticle

Bartuzi, P, Billadeau, DD, Favier, R, Rong, S, Dekker, D, Fedoseienko, A, Fieten, H, Wijers, M, Levels, JH, Huijkman, N, Kloosterhuis, N, Van Der Molen, H, Brufau, G, Groen, AK, Elliott, AM, Kuivenhoven, JA, Plecko, B, Grangl, G, McGaughran, J, Horton, JD, Burstein, E, Hofker, MH & Van De Sluis, B 2016, 'CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL', Nature Communications, vol. 7, 10961. https://doi.org/10.1038/ncomms10961
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. / CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. In: Nature Communications. 2016 ; Vol. 7.
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AU - Dekker, Daphne

AU - Fedoseienko, Alina

AU - Fieten, Hille

AU - Wijers, Melinde

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AU - Elliott, Alison M.

AU - Kuivenhoven, Jan Albert

AU - Plecko, Barbara

AU - Grangl, Gernot

AU - McGaughran, Julie

AU - Horton, Jay D.

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AU - Hofker, Marten H.

AU - Van De Sluis, Bart

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