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 Horton; Ezra Burstein; Marten H Hofker; Bart van de Sluis

doi:10.1038/ncomms10961

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 journal › Article › Academic › peer-review

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 language	English
Article number	10961
Journal	Nature Communications [E]
Volume	7
DOIs	https://doi.org/10.1038/ncomms10961
Publication status	Published - 11 Mar 2016

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Bartuzi, P., Billadeau, D. D., Favier, R., Rong, S., Dekker, D., Fedoseienko, A., Fieten, H., Wijers, M., Levels, J. H., Huijkman, N., Kloosterhuis, N., van der Molen, H., Brufau, G., Groen, A. K., Elliott, A. M., Kuivenhoven, J. A., Plecko, B., Grangl, G., McGaughran, J., ... van de Sluis, B. (2016). CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nature Communications [E], 7, Article 10961. https://doi.org/10.1038/ncomms10961

@article{c8ab78b8675b43d19babc8c68058ffb9,

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",

year = "2016",

month = mar,

day = "11",

doi = "10.1038/ncomms10961",

language = "English",

volume = "7",

journal = "Nature Communications [E]",

issn = "2041-1723",

publisher = "Nature Research",

}

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 [E], vol. 7, 10961. https://doi.org/10.1038/ncomms10961

TY - JOUR

T1 - CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL

AU - Bartuzi, Paulina

AU - Billadeau, Daniel D

AU - Favier, Robert

AU - Rong, Shunxing

AU - Dekker, Daphne

AU - Fedoseienko, Alina

AU - Fieten, Hille

AU - Wijers, Melinde

AU - Levels, Johannes H

AU - Huijkman, Nicolette

AU - Kloosterhuis, Niels

AU - van der Molen, Henk

AU - Brufau, Gemma

AU - Groen, Albert K

AU - Elliott, Alison M

AU - Kuivenhoven, Jan Albert

AU - Plecko, Barbara

AU - Grangl, Gernot

AU - McGaughran, Julie

AU - Horton, Jay D

AU - Burstein, Ezra

AU - Hofker, Marten H

AU - van de Sluis, Bart

PY - 2016/3/11

Y1 - 2016/3/11

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms10961

DO - 10.1038/ncomms10961

M3 - Article

C2 - 26965651

SN - 2041-1723

VL - 7

JO - Nature Communications [E]

JF - Nature Communications [E]

M1 - 10961

ER -

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

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