CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL
Identifieur interne : 000198 ( Pmc/Curation ); précédent : 000197; suivant : 000199CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL
Auteurs : Paulina Bartuzi [Pays-Bas] ; Daniel D. Billadeau [États-Unis] ; Robert Favier [Pays-Bas] ; Shunxing Rong [États-Unis] ; Daphne Dekker [Pays-Bas] ; Alina Fedoseienko [Pays-Bas] ; Hille Fieten [Pays-Bas] ; Melinde Wijers [Pays-Bas] ; Johannes H. Levels [Pays-Bas] ; Nicolette Huijkman [Pays-Bas] ; Niels Kloosterhuis [Pays-Bas] ; Henk Van Der Molen [Pays-Bas] ; Gemma Brufau [Pays-Bas] ; Albert K. Groen [Pays-Bas] ; Alison M. Elliott [Canada] ; Jan Albert Kuivenhoven [Pays-Bas] ; Barbara Plecko [Autriche, Suisse] ; Gernot Grangl [Autriche] ; Julie Mcgaughran [Australie] ; Jay D. Horton [États-Unis] ; Ezra Burstein [États-Unis] ; Marten H. Hofker [Pays-Bas] ; Bart Van De Sluis [Pays-Bas]Source :
- Nature Communications [ 2041-1723 ] ; 2016.
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
Url:
DOI: 10.1038/ncomms10961
PubMed: 26965651
PubMed Central: 4792963
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Billadeau</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic</institution>, 200 First Street Southwest, Rochester, Minnesota 55905, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>, 200 First Street Southwest, Rochester, Minnesota 55905</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic</institution>, 200 First Street Southwest, Rochester, Minnesota 55905,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Favier, Robert" sort="Favier, Robert" uniqKey="Favier R" first="Robert" last="Favier">Robert Favier</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University</institution>, Yalelaan 108, 3584 CM Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rong, Shunxing" sort="Rong, Shunxing" uniqKey="Rong S" first="Shunxing" last="Rong">Shunxing Rong</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Molecular Genetics, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dekker, Daphne" sort="Dekker, Daphne" uniqKey="Dekker D" first="Daphne" last="Dekker">Daphne Dekker</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fedoseienko, Alina" sort="Fedoseienko, Alina" uniqKey="Fedoseienko A" first="Alina" last="Fedoseienko">Alina Fedoseienko</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fieten, Hille" sort="Fieten, Hille" uniqKey="Fieten H" first="Hille" last="Fieten">Hille Fieten</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University</institution>, Yalelaan 108, 3584 CM Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wijers, Melinde" sort="Wijers, Melinde" uniqKey="Wijers M" first="Melinde" last="Wijers">Melinde Wijers</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Levels, Johannes H" sort="Levels, Johannes H" uniqKey="Levels J" first="Johannes H." last="Levels">Johannes H. Levels</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam</institution>, Meibergdreef 9, 1105 AZ Amsterdam,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Huijkman, Nicolette" sort="Huijkman, Nicolette" uniqKey="Huijkman N" first="Nicolette" last="Huijkman">Nicolette Huijkman</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kloosterhuis, Niels" sort="Kloosterhuis, Niels" uniqKey="Kloosterhuis N" first="Niels" last="Kloosterhuis">Niels Kloosterhuis</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Der Molen, Henk" sort="Van Der Molen, Henk" uniqKey="Van Der Molen H" first="Henk" last="Van Der Molen">Henk Van Der Molen</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brufau, Gemma" sort="Brufau, Gemma" uniqKey="Brufau G" first="Gemma" last="Brufau">Gemma Brufau</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Department of Pediatrics, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Groen, Albert K" sort="Groen, Albert K" uniqKey="Groen A" first="Albert K." last="Groen">Albert K. Groen</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Department of Pediatrics, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Elliott, Alison M" sort="Elliott, Alison M" uniqKey="Elliott A" first="Alison M." last="Elliott">Alison M. Elliott</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Medical Genetics, University of British Columbia</institution>, 4500 Oak Street, Vancouver, British Columbia,<country>Canada</country> V6H 3N1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kuivenhoven, Jan Albert" sort="Kuivenhoven, Jan Albert" uniqKey="Kuivenhoven J" first="Jan Albert" last="Kuivenhoven">Jan Albert Kuivenhoven</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Plecko, Barbara" sort="Plecko, Barbara" uniqKey="Plecko B" first="Barbara" last="Plecko">Barbara Plecko</name><affiliation wicri:level="1"><nlm:aff id="a9"><institution>Department of Pediatrics and Adolescence Medicine, Division of Child Neurology, Medical University Graz</institution>, Auenbruggerplatz 2, A-8036 Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Division of Child Neurology, University Children's Hospital</institution>, Steinwiesstrasse 75, CH-8032 Zurich,<country>Switzerland</country></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Grangl, Gernot" sort="Grangl, Gernot" uniqKey="Grangl G" first="Gernot" last="Grangl">Gernot Grangl</name><affiliation wicri:level="1"><nlm:aff id="a9"><institution>Department of Pediatrics and Adolescence Medicine, Division of Child Neurology, Medical University Graz</institution>, Auenbruggerplatz 2, A-8036 Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mcgaughran, Julie" sort="Mcgaughran, Julie" uniqKey="Mcgaughran J" first="Julie" last="Mcgaughran">Julie Mcgaughran</name><affiliation wicri:level="1"><nlm:aff id="a11"><institution>Genetic Health Queensland at the Royal Brisbane and Women's Hospital, Herston, University of Queensland</institution>, Herston, Brisbane, Queensland 4029,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a12"><institution>School of Medicine, University of Queensland</institution>, Herston, Brisbane, Queensland 4029,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Horton, Jay D" sort="Horton, Jay D" uniqKey="Horton J" first="Jay D." last="Horton">Jay D. Horton</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Molecular Genetics, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Department of Internal Medicine, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Burstein, Ezra" sort="Burstein, Ezra" uniqKey="Burstein E" first="Ezra" last="Burstein">Ezra Burstein</name><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Department of Internal Medicine, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a14"><institution>Department of Molecular Biology, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hofker, Marten H" sort="Hofker, Marten H" uniqKey="Hofker M" first="Marten H." last="Hofker">Marten H. Hofker</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van De Sluis, Bart" sort="Van De Sluis, Bart" uniqKey="Van De Sluis B" first="Bart" last="Van De Sluis">Bart Van De Sluis</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26965651</idno><idno type="pmc">4792963</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792963</idno><idno type="RBID">PMC:4792963</idno><idno type="doi">10.1038/ncomms10961</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000198</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000198</idno><idno type="wicri:Area/Pmc/Curation">000198</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000198</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL</title><author><name sortKey="Bartuzi, Paulina" sort="Bartuzi, Paulina" uniqKey="Bartuzi P" first="Paulina" last="Bartuzi">Paulina Bartuzi</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Billadeau, Daniel D" sort="Billadeau, Daniel D" uniqKey="Billadeau D" first="Daniel D." last="Billadeau">Daniel D. Billadeau</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic</institution>, 200 First Street Southwest, Rochester, Minnesota 55905, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>, 200 First Street Southwest, Rochester, Minnesota 55905</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic</institution>, 200 First Street Southwest, Rochester, Minnesota 55905,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Favier, Robert" sort="Favier, Robert" uniqKey="Favier R" first="Robert" last="Favier">Robert Favier</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University</institution>, Yalelaan 108, 3584 CM Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rong, Shunxing" sort="Rong, Shunxing" uniqKey="Rong S" first="Shunxing" last="Rong">Shunxing Rong</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Molecular Genetics, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dekker, Daphne" sort="Dekker, Daphne" uniqKey="Dekker D" first="Daphne" last="Dekker">Daphne Dekker</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fedoseienko, Alina" sort="Fedoseienko, Alina" uniqKey="Fedoseienko A" first="Alina" last="Fedoseienko">Alina Fedoseienko</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fieten, Hille" sort="Fieten, Hille" uniqKey="Fieten H" first="Hille" last="Fieten">Hille Fieten</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University</institution>, Yalelaan 108, 3584 CM Utrecht,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wijers, Melinde" sort="Wijers, Melinde" uniqKey="Wijers M" first="Melinde" last="Wijers">Melinde Wijers</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Levels, Johannes H" sort="Levels, Johannes H" uniqKey="Levels J" first="Johannes H." last="Levels">Johannes H. Levels</name><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam</institution>, Meibergdreef 9, 1105 AZ Amsterdam,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Huijkman, Nicolette" sort="Huijkman, Nicolette" uniqKey="Huijkman N" first="Nicolette" last="Huijkman">Nicolette Huijkman</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kloosterhuis, Niels" sort="Kloosterhuis, Niels" uniqKey="Kloosterhuis N" first="Niels" last="Kloosterhuis">Niels Kloosterhuis</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van Der Molen, Henk" sort="Van Der Molen, Henk" uniqKey="Van Der Molen H" first="Henk" last="Van Der Molen">Henk Van Der Molen</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Brufau, Gemma" sort="Brufau, Gemma" uniqKey="Brufau G" first="Gemma" last="Brufau">Gemma Brufau</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Department of Pediatrics, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Groen, Albert K" sort="Groen, Albert K" uniqKey="Groen A" first="Albert K." last="Groen">Albert K. Groen</name><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Department of Pediatrics, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Elliott, Alison M" sort="Elliott, Alison M" uniqKey="Elliott A" first="Alison M." last="Elliott">Alison M. Elliott</name><affiliation wicri:level="1"><nlm:aff id="a8"><institution>Department of Medical Genetics, University of British Columbia</institution>, 4500 Oak Street, Vancouver, British Columbia,<country>Canada</country> V6H 3N1</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kuivenhoven, Jan Albert" sort="Kuivenhoven, Jan Albert" uniqKey="Kuivenhoven J" first="Jan Albert" last="Kuivenhoven">Jan Albert Kuivenhoven</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Plecko, Barbara" sort="Plecko, Barbara" uniqKey="Plecko B" first="Barbara" last="Plecko">Barbara Plecko</name><affiliation wicri:level="1"><nlm:aff id="a9"><institution>Department of Pediatrics and Adolescence Medicine, Division of Child Neurology, Medical University Graz</institution>, Auenbruggerplatz 2, A-8036 Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a10"><institution>Division of Child Neurology, University Children's Hospital</institution>, Steinwiesstrasse 75, CH-8032 Zurich,<country>Switzerland</country></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Grangl, Gernot" sort="Grangl, Gernot" uniqKey="Grangl G" first="Gernot" last="Grangl">Gernot Grangl</name><affiliation wicri:level="1"><nlm:aff id="a9"><institution>Department of Pediatrics and Adolescence Medicine, Division of Child Neurology, Medical University Graz</institution>, Auenbruggerplatz 2, A-8036 Graz,<country>Austria</country></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mcgaughran, Julie" sort="Mcgaughran, Julie" uniqKey="Mcgaughran J" first="Julie" last="Mcgaughran">Julie Mcgaughran</name><affiliation wicri:level="1"><nlm:aff id="a11"><institution>Genetic Health Queensland at the Royal Brisbane and Women's Hospital, Herston, University of Queensland</institution>, Herston, Brisbane, Queensland 4029,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a12"><institution>School of Medicine, University of Queensland</institution>, Herston, Brisbane, Queensland 4029,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Horton, Jay D" sort="Horton, Jay D" uniqKey="Horton J" first="Jay D." last="Horton">Jay D. Horton</name><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Department of Molecular Genetics, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Department of Internal Medicine, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Burstein, Ezra" sort="Burstein, Ezra" uniqKey="Burstein E" first="Ezra" last="Burstein">Ezra Burstein</name><affiliation wicri:level="1"><nlm:aff id="a13"><institution>Department of Internal Medicine, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a14"><institution>Department of Molecular Biology, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hofker, Marten H" sort="Hofker, Marten H" uniqKey="Hofker M" first="Marten H." last="Hofker">Marten H. Hofker</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Van De Sluis, Bart" sort="Van De Sluis, Bart" uniqKey="Van De Sluis B" first="Bart" last="Van De Sluis">Bart Van De Sluis</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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 <italic>CCDC22</italic> are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific <italic>Commd1</italic> knockout mice have elevated plasma LDL cholesterol levels. Furthermore, <italic>Commd1</italic> 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 <italic>KIAA0196</italic> (strumpellin) is associated with hypercholesterolaemia in humans. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26965651</article-id><article-id pub-id-type="pmc">4792963</article-id><article-id pub-id-type="pii">ncomms10961</article-id><article-id pub-id-type="doi">10.1038/ncomms10961</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Bartuzi</surname><given-names>Paulina</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Billadeau</surname><given-names>Daniel D.</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Favier</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Rong</surname><given-names>Shunxing</given-names></name><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Dekker</surname><given-names>Daphne</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fedoseienko</surname><given-names>Alina</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fieten</surname><given-names>Hille</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Wijers</surname><given-names>Melinde</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Levels</surname><given-names>Johannes H.</given-names></name><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Huijkman</surname><given-names>Nicolette</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kloosterhuis</surname><given-names>Niels</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>van der Molen</surname><given-names>Henk</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Brufau</surname><given-names>Gemma</given-names></name><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Groen</surname><given-names>Albert K.</given-names></name><xref ref-type="aff" rid="a7">7</xref></contrib><contrib contrib-type="author"><name><surname>Elliott</surname><given-names>Alison M.</given-names></name><xref ref-type="aff" rid="a8">8</xref></contrib><contrib contrib-type="author"><name><surname>Kuivenhoven</surname><given-names>Jan Albert</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Plecko</surname><given-names>Barbara</given-names></name><xref ref-type="aff" rid="a9">9</xref><xref ref-type="aff" rid="a10">10</xref></contrib><contrib contrib-type="author"><name><surname>Grangl</surname><given-names>Gernot</given-names></name><xref ref-type="aff" rid="a9">9</xref></contrib><contrib contrib-type="author"><name><surname>McGaughran</surname><given-names>Julie</given-names></name><xref ref-type="aff" rid="a11">11</xref><xref ref-type="aff" rid="a12">12</xref></contrib><contrib contrib-type="author"><name><surname>Horton</surname><given-names>Jay D.</given-names></name><xref ref-type="aff" rid="a5">5</xref><xref ref-type="aff" rid="a13">13</xref></contrib><contrib contrib-type="author"><name><surname>Burstein</surname><given-names>Ezra</given-names></name><xref ref-type="aff" rid="a13">13</xref><xref ref-type="aff" rid="a14">14</xref></contrib><contrib contrib-type="author"><name><surname>Hofker</surname><given-names>Marten H.</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>van de Sluis</surname><given-names>Bart</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref></contrib><aff id="a1"><label>1</label><institution>Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></aff><aff id="a2"><label>2</label><institution>Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic</institution>, 200 First Street Southwest, Rochester, Minnesota 55905, USA</aff><aff id="a3"><label>3</label><institution>Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic</institution>, 200 First Street Southwest, Rochester, Minnesota 55905,<country>USA</country></aff><aff id="a4"><label>4</label><institution>Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University</institution>, Yalelaan 108, 3584 CM Utrecht,<country>The Netherlands</country></aff><aff id="a5"><label>5</label><institution>Department of Molecular Genetics, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></aff><aff id="a6"><label>6</label><institution>Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam</institution>, Meibergdreef 9, 1105 AZ Amsterdam,<country>The Netherlands</country></aff><aff id="a7"><label>7</label><institution>Department of Pediatrics, University of Groningen, University Medical Center Groningen</institution>, Antonius Deusinglaan 1, 9713 AV Groningen,<country>The Netherlands</country></aff><aff id="a8"><label>8</label><institution>Department of Medical Genetics, University of British Columbia</institution>, 4500 Oak Street, Vancouver, British Columbia,<country>Canada</country> V6H 3N1</aff><aff id="a9"><label>9</label><institution>Department of Pediatrics and Adolescence Medicine, Division of Child Neurology, Medical University Graz</institution>, Auenbruggerplatz 2, A-8036 Graz,<country>Austria</country></aff><aff id="a10"><label>10</label><institution>Division of Child Neurology, University Children's Hospital</institution>, Steinwiesstrasse 75, CH-8032 Zurich,<country>Switzerland</country></aff><aff id="a11"><label>11</label><institution>Genetic Health Queensland at the Royal Brisbane and Women's Hospital, Herston, University of Queensland</institution>, Herston, Brisbane, Queensland 4029,<country>Australia</country></aff><aff id="a12"><label>12</label><institution>School of Medicine, University of Queensland</institution>, Herston, Brisbane, Queensland 4029,<country>Australia</country></aff><aff id="a13"><label>13</label><institution>Department of Internal Medicine, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></aff><aff id="a14"><label>14</label><institution>Department of Molecular Biology, University of Texas Southwestern Medical Center</institution>, 5323 Harry Hines Boulevard, Dallas, Texas 75390,<country>USA</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>a.j.a.van.de.sluis@umcg.nl</email></corresp></author-notes><pub-date pub-type="epub"><day>11</day><month>03</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>7</volume><elocation-id>10961</elocation-id><history><date date-type="received"><day>18</day><month>11</month><year>2015</year></date><date date-type="accepted"><day>04</day><month>02</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>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 <italic>CCDC22</italic> are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific <italic>Commd1</italic> knockout mice have elevated plasma LDL cholesterol levels. Furthermore, <italic>Commd1</italic> 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 <italic>KIAA0196</italic> (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.</p></abstract><abstract abstract-type="web-summary"><p><inline-graphic id="i1" xlink:href="ncomms10961-i1.jpg"></inline-graphic>Low density lipoprotein receptor (LDLR) is crucial for cholesterol homeostasis. Here, the authors show that components of the CCC-protein complex, CCDC22 and COMMD1, facilitate the endosomal sorting of LDLR and that mutations in these genes cause hypercholesterolemia in dogs and mice, providing new insights into regulation of cholesterol homeostasis.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>COMMD1-deficient dogs are hypercholesterolaemic.</title><p>(<bold>a</bold>) Western blot analysis of COMMD1, CCDC22 and CCDC93 in livers from an unaffected dog (<italic>COMMD1</italic><sup>+/+</sup>) and an affected dog homozygous for a loss-of-function mutation in <italic>COMMD1</italic> (<italic>COMMD1</italic><sup><italic>−/−</italic></sup>). (<bold>b</bold>) Plasma TC and (<bold>c</bold>) TG levels of dogs heterozygous (+/−) (<italic>n</italic>=5) or homozygous (−/−) (<italic>n</italic>=4) for a <italic>COMMD1</italic> mutation (<bold>d</bold>) FPLC lipoprotein profile of <italic>COMMD1</italic><sup><italic>+/−</italic></sup> (<italic>n</italic>=5) and <italic>COMMD1</italic><sup><italic>−/−</italic></sup> dogs (<italic>n</italic>=4). Pooled plasma samples of each experimental group were separated using FPLC gel filtration. Fifty fractions were collected from each separation. TC content was determined and lipoprotein profile was plotted. The results are presented as mean±s.e.m., and significance was calculated relative to the control group by unpaired Student's <italic>t</italic>-test; *<italic>P</italic><0.05.</p></caption><graphic xlink:href="ncomms10961-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Ablation of hepatic <italic>Commd1</italic> increases plasma total and LDL cholesterol levels.</title><p>(<bold>a</bold>) Plasma TC and (<bold>b</bold>) TG levels of hepatic <italic>Commd1</italic> knockout mice (<italic>Commd1</italic><sup>ΔHep</sup>) and WT mice (<italic>n</italic>=6–8) fed a chow diet or a HFC (0.2%) diet for 20 weeks. Pooled plasma samples of each experimental group of mice fed either the (<bold>c</bold>) chow or (<bold>d</bold>) the HFC diet were separated using FPLC gel filtration. Fifty fractions were collected from each separation. TC content was determined and lipoprotein profile was plotted. Fractions #13–26 containing cholesterol were collected and loaded on an SDS polyacrylamide gel and blotted using antibodies against apoA1 and apoB100 lipoproteins. The chow group (<bold>e</bold>) and HFC group (<bold>f</bold>) are shown. (<bold>g</bold>) Livers of chow-fed mice were homogenized, and 30 μg of protein was subjected to immunoblot analysis. Levels of LDLR, LRP1, ARH, CCDC22, CCDC93 and tubulin were determined. Three representative samples from WT and <italic>Commd1</italic><sup>ΔHep</sup> mice are shown. (<bold>h</bold>) Relative levels of the proteins shown in <bold>g</bold> were determined by immunoblot analysis, and densitometry analysis was performed using tubulin as a loading control (<italic>n</italic>=6–8 per genotype). The results are presented as mean±s.e.m., and significance was calculated relative to the control group by unpaired Student's <italic>t</italic>-test; ***<italic>P</italic><0.001. ARH, autosomal recessive hypercholesterolaemia protein.</p></caption><graphic xlink:href="ncomms10961-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>LDLR associates with COMMD1 and the WASH complex.</title><p>(<bold>a</bold>) Human embryonic kidney 293T (HEK293T) cells were transfected with constructs expressing Flag-LDLR with either COMMD1-GST or GST alone. Interaction with COMMD1 was detected via pull-down assay using glutathione sepharose beads. (<bold>b</bold>) HEK293T cells were transfected with Flag-LDLR vector, and interaction with endogenous COMMD1 was detected by immunoprecipitation with rabbit anti-Flag-antibody. (<bold>c</bold>) Colocalization of LDLR (red) and COMMD1 (green) in <italic>Commd1</italic><sup>f/f</sup> MEFs examined by immunofluorescence staining. Representative images are shown; scale bar, 5μm. LDLR (red) and COMMD1 (green) was stained in COMMD1-deficient MEFs (<italic>Commd1</italic><sup><italic>−/−</italic></sup>) and imaged by confocal fluorescence microscopy. COMMD1 levels in <italic>Commd1</italic><sup>f/f</sup> and in <italic>Commd1</italic><sup><italic>−/−</italic></sup> MEFs determined by immunoblot analysis. (<bold>d</bold>) Liver of a WT chow-fed mouse was homogenized and loaded on a continuous 10–40% sucrose gradient. Fractions were separated by ultracentrifugation and immunoblotted using antibodies against COMMD1, LDLR, WASH1, FAM21, VPS35 and CCDC22. The figure represents results of three independent experiments. (<bold>e</bold>) HEK293T cells were transfected with Ha-COMMD1 construct together with GST alone, GST-LDLRct (GST-tagged cytosolic domain of LDLR) or GST-LDLRct Y807A (GST-tagged mutated cytosolic domain of LDLR). Pull-down assay was performed to study the interaction between LDLRct and COMMD1. (<bold>f</bold>) Lysates of Flag-LDLR-transfected HEK293T cells were used for immunoprecipitation assays. Immunoprecipitates were washed, separated by SDS–polyacrylamide gel electrophoresis and immunoblotted as indicated.</p></caption><graphic xlink:href="ncomms10961-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>COMMD1 deficiency impairs the function of LDLR.</title><p>(<bold>a</bold>) LDLR (green), COMMD1 (red) and VPS35 (pink) were stained in <italic>Commd1</italic><sup>f/f</sup> and <italic>Commd1</italic><sup><italic>−/−</italic></sup> MEFs and imaged by confocal microscopy. Representative images are shown; scale bar, 5μm. (<bold>b</bold>) Quantification of the colocalization of LDLR with COMMD1, VPS35, EEA1 and LAMP1 was performed by the analysis of 30–40 cells. (<bold>c</bold>) Total and plasma membrane LDLR levels of <italic>Commd1</italic><sup>f/f</sup> and <italic>Commd1</italic><sup><italic>−/−</italic></sup> MEFs determined by biotinylation assay. Data represent three independent experiments, and (<bold>d</bold>) the relative levels of LDLR at the cell surface are quantified in all experiments. (<bold>e</bold>) <italic>In vitro</italic> LDL and transferrin uptake assay. Dil-labelled LDL (5 μg ml<sup>−1</sup>) or Alexa-633-labelled transferrin (5 μg ml<sup>−1</sup>) was added to serum-depleted medium and incubated with MEFs at 4 °C for 1 h and subsequently at 37 °C for 5 min. Dil-labelled LDL and Alexa-633-labelled transferrin uptake was measured by FACS analysis, and the relative uptake in triplicate is shown. The results are presented as mean±s.e.m.; significance was calculated relative to the control group by unpaired Student's <italic>t</italic>-test; *<italic>P</italic><0.05, ***<italic>P</italic><0.001.</p></caption><graphic xlink:href="ncomms10961-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>The WASH complex is essential for endosomal sorting of LDLR.</title><p>(<bold>a</bold>) Cellular localization of LDLR (green), COMMD1 (red) and LAMP1 (pink) in <italic>Wash1</italic><sup>f/f</sup> and <italic>Wash1</italic><sup><italic>−/−</italic></sup> MEFs was determined by immunofluorescence staining. Representative images are shown; scale bar, 5 μm. Relative colocalization of (<bold>b</bold>) LDLR and (<bold>c</bold>) COMMD1 with VPS35, EEA1 and LAMP1 was quantified. (<bold>d</bold>) LDLR, WASH1, VPS35 and COMMD1 levels in <italic>Wash1</italic><sup>f/f</sup> and <italic>Wash1</italic><sup><italic>−/−</italic></sup> MEFs analysed by western blot. (<bold>e</bold>) Representative images (<italic>n</italic>=3) of immunoblot analysis of total LDLR levels in <italic>Wash1</italic><sup>f/f</sup> and <italic>Wash1</italic><sup><italic>−/−</italic></sup> MEFs treated with bafilomycin A (100 nM) for 0, 4 and 6 h. (<bold>f</bold>) Densitometry revealed the relative levels of LDLR in bafilomycin A-treated cells (<italic>n</italic>=3). (<bold>g</bold>) Representative images (<italic>n</italic>=3) of LDLR on the surface of <italic>Wash1</italic><sup>f/f</sup> and <italic>Wash1</italic><sup><italic>−/−</italic></sup> MEFs determined by surface biotinylation assay. (<bold>h</bold>) Densitometry revealed relative LDLR surface levels (<italic>n</italic>=3). (<bold>i</bold>) <italic>Wash1</italic><sup>f/f</sup> and <italic>Wash1</italic><sup><italic>−/−</italic></sup> MEFs were incubated with DiI-LDL for 30 min and imaged by fluorescence microscope. (<bold>j</bold>) Fluorescence intensity was quantified using ImageJ software and was normalized to the number of DAPI nuclei per image; >30 cells per condition were recorded. The results are presented as mean±s.e.m.; significance was calculated relative to the control group by unpaired Student's <italic>t</italic>-test; ***<italic>P</italic><0.001.</p></caption><graphic xlink:href="ncomms10961-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title>Hypothetical model of CCC- and WASH-mediated endosomal LDLR sorting.</title><p>After internalization mediated by ARH, LDLR is sorted in endosomes<xref ref-type="bibr" rid="b58">58</xref>. LDLR is directed to the lysosome for proteolysis—which is induced by either PCSK9 (refs <xref ref-type="bibr" rid="b59">59</xref>, <xref ref-type="bibr" rid="b60">60</xref>) or IDOL<xref ref-type="bibr" rid="b61">61</xref>—or retrieved and recycled back to the cell surface. SNX17 enhances LDL endocytosis likely by promoting LDLR retrieval<xref ref-type="bibr" rid="b44">44</xref>, which might precede CCC and retromer/WASH-mediated endosomal trafficking. Through the interaction of the retromer component VPS35 with FAM21 the WASH complex and the CCC complex are recruited to the endosomes<xref ref-type="bibr" rid="b2">2</xref><xref ref-type="bibr" rid="b4">4</xref><xref ref-type="bibr" rid="b8">8</xref>. Subsequently, CCC and WASH form a protein complex with LDLR; WASH facilitates the formation of branched actin patches to define restricted domains of the endosomes<xref ref-type="bibr" rid="b62">62</xref> from where LDLR is sorted back to the cell surface. NDRG1 is required for the formation of MVB: loss of NDRG1 impairs LDL uptake and LDLR recycling, and causes the accumulation of IDOL-mediated ubiquitinated LDLR in MVB<xref ref-type="bibr" rid="b48">48</xref>. Further research is needed to assess whether CCC and WASH are functionally related to SNX17, NDRG1 and to the lysosomal degradation pathways of LDLR. ARH, autosomal recessive hypercholesterolaemia protein; MVB, multivesicular body; PCSK9, proprotein convertase subtilisin/kexin type 9; Ub, ubiquitin; WASH, WASH1, FAM21, strumpellin, KIAA1033, CCDC53.</p></caption><graphic xlink:href="ncomms10961-f6"></graphic></fig><table-wrap position="float" id="t1"><label>Table 1</label><caption><title>Plasma lipid levels of individuals with mutations in <italic>CCDC22</italic>.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col></colgroup><tbody valign="top"><tr><td align="center" valign="top" charoff="50"><inline-graphic id="i2" xlink:href="ncomms10961-i2.jpg"></inline-graphic></td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>DOB, date of birth; ND, not determined.</p></fn><fn id="t1-fn2"><p>In red levels >95th percentiles corrected for age and gender. The age is indicated at the moment of clinical evaluation.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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