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

被引：176

作者：

Bartuzi, Paulina ^{[1
]}

Billadeau, Daniel D. ^{[2
,3
]}

Favier, Robert ^{[4
]}

Rong, Shunxing ^{[5
]}

Dekker, Daphne ^{[1
]}

Fedoseienko, Alina ^{[1
]}

Fieten, Hille ^{[4
]}

Wijers, Melinde ^{[1
]}

Levels, Johannes H. ^{[6
]}

Huijkman, Nicolette ^{[1
]}

Kloosterhuis, Niels ^{[1
]}

van der Molen, Henk ^{[1
]}

Brufau, Gemma ^{[7
]}

Groen, Albert K. ^{[7
]}

Elliott, Alison M. ^{[8
]}

Kuivenhoven, Jan Albert ^{[1
]}

Plecko, Barbara ^{[9
,10
]}

Grangl, Gernot ^{[9
]}

McGaughran, Julie ^{[11
,12
]}

Horton, Jay D. ^{[5
,13
]}

Burstein, Ezra ^{[13
,14
]}

Hofker, Marten H. ^{[1
]}

van de Sluis, Bart ^{[1
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Mol Genet Sect, Antonius Deusinglaan 1, NL-9713 AV Groningen, Netherlands

[2] Mayo Clin, Coll Med, Dept Immunol, 200 First St Southwest, Rochester, MN 55905 USA

[3] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, 200 First St Southwest, Rochester, MN 55905 USA

[4] Univ Utrecht, Fac Vet Med, Dept Clin Sci Compan Anim, Yalelaan 108, NL-3584 CM Utrecht, Netherlands

[5] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

[6] Univ Amsterdam, Acad Med Ctr, Dept Vasc & Expt Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[7] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat, Antonius Deusinglaan 1, NL-9713 AV Groningen, Netherlands

[8] Univ British Columbia, Dept Med Genet, 4500 Oak St, Vancouver, BC V6H 3N1, Canada

[9] Med Univ Graz, Dept Pediat & Adolescence Med, Div Child Neurol, Auenbruggerpl 2, A-8036 Graz, Austria

[10] Univ Childrens Hosp, Div Child Neurol, Steinwiesstr 75, CH-8032 Zurich, Switzerland

[11] Univ Queensland, Royal Brisbane & Womens Hosp, Genet Hlth Queensland, Brisbane, Qld 4029, Australia

[12] Univ Queensland, Sch Med, Brisbane, Qld 4029, Australia

[13] Univ Texas SW Med Ctr Dallas, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

[14] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

LOW-DENSITY-LIPOPROTEIN; FAMILIAL HYPERCHOLESTEROLEMIA; LIPID-METABOLISM; RECEPTOR; COMPLEX; CHOLESTEROL; COPPER; GENE; IDENTIFICATION; TRAFFICKING;

D O I：

10.1038/ncomms10961

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：11

共 62 条

[1]

Metabolism of cholesterol ester of apolipoprotein B100-containing lipoproteins in dogs: evidence for disregarding cholesterol ester transfer [J].