Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.

In prion diseases, the cellular form of the prion protein, PrP(C), undergoes a conformational conversion to the infectious isoform, PrP(Sc). PrP(C) associates with lipid rafts through its glycosyl-phosphatidylinositol (GPI) anchor and a region in its N-terminal domain which also binds to heparan sul...

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Autores principales:	David R Taylor, Isobel J Whitehouse, Nigel M Hooper
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b15ee03296e644a5a7bad0b61f71d9dd
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spelling	oai:doaj.org-article:b15ee03296e644a5a7bad0b61f71d9dd2021-12-02T19:59:45ZGlypican-1 mediates both prion protein lipid raft association and disease isoform formation.1553-73661553-737410.1371/journal.ppat.1000666https://doaj.org/article/b15ee03296e644a5a7bad0b61f71d9dd2009-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19936054/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374In prion diseases, the cellular form of the prion protein, PrP(C), undergoes a conformational conversion to the infectious isoform, PrP(Sc). PrP(C) associates with lipid rafts through its glycosyl-phosphatidylinositol (GPI) anchor and a region in its N-terminal domain which also binds to heparan sulfate proteoglycans (HSPGs). We show that heparin displaces PrP(C) from rafts and promotes its endocytosis, suggesting that heparin competes with an endogenous raft-resident HSPG for binding to PrP(C). We then utilised a transmembrane-anchored form of PrP (PrP-TM), which is targeted to rafts solely by its N-terminal domain, to show that both heparin and phosphatidylinositol-specific phospholipase C can inhibit its association with detergent-resistant rafts, implying that a GPI-anchored HSPG targets PrP(C) to rafts. Depletion of the major neuronal GPI-anchored HSPG, glypican-1, significantly reduced the raft association of PrP-TM and displaced PrP(C) from rafts, promoting its endocytosis. Glypican-1 and PrP(C) colocalised on the cell surface and both PrP(C) and PrP(Sc) co-immunoprecipitated with glypican-1. Critically, treatment of scrapie-infected N2a cells with glypican-1 siRNA significantly reduced PrP(Sc) formation. In contrast, depletion of glypican-1 did not alter the inhibitory effect of PrP(C) on the beta-secretase cleavage of the Alzheimer's amyloid precursor protein. These data indicate that glypican-1 is a novel cellular cofactor for prion conversion and we propose that it acts as a scaffold facilitating the interaction of PrP(C) and PrP(Sc) in lipid rafts.David R TaylorIsobel J WhitehouseNigel M HooperPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 11, p e1000666 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 David R Taylor Isobel J Whitehouse Nigel M Hooper Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
description	In prion diseases, the cellular form of the prion protein, PrP(C), undergoes a conformational conversion to the infectious isoform, PrP(Sc). PrP(C) associates with lipid rafts through its glycosyl-phosphatidylinositol (GPI) anchor and a region in its N-terminal domain which also binds to heparan sulfate proteoglycans (HSPGs). We show that heparin displaces PrP(C) from rafts and promotes its endocytosis, suggesting that heparin competes with an endogenous raft-resident HSPG for binding to PrP(C). We then utilised a transmembrane-anchored form of PrP (PrP-TM), which is targeted to rafts solely by its N-terminal domain, to show that both heparin and phosphatidylinositol-specific phospholipase C can inhibit its association with detergent-resistant rafts, implying that a GPI-anchored HSPG targets PrP(C) to rafts. Depletion of the major neuronal GPI-anchored HSPG, glypican-1, significantly reduced the raft association of PrP-TM and displaced PrP(C) from rafts, promoting its endocytosis. Glypican-1 and PrP(C) colocalised on the cell surface and both PrP(C) and PrP(Sc) co-immunoprecipitated with glypican-1. Critically, treatment of scrapie-infected N2a cells with glypican-1 siRNA significantly reduced PrP(Sc) formation. In contrast, depletion of glypican-1 did not alter the inhibitory effect of PrP(C) on the beta-secretase cleavage of the Alzheimer's amyloid precursor protein. These data indicate that glypican-1 is a novel cellular cofactor for prion conversion and we propose that it acts as a scaffold facilitating the interaction of PrP(C) and PrP(Sc) in lipid rafts.
format	article
author	David R Taylor Isobel J Whitehouse Nigel M Hooper
author_facet	David R Taylor Isobel J Whitehouse Nigel M Hooper
author_sort	David R Taylor
title	Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
title_short	Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
title_full	Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
title_fullStr	Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
title_full_unstemmed	Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
title_sort	glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/b15ee03296e644a5a7bad0b61f71d9dd
work_keys_str_mv	AT davidrtaylor glypican1mediatesbothprionproteinlipidraftassociationanddiseaseisoformformation AT isobeljwhitehouse glypican1mediatesbothprionproteinlipidraftassociationanddiseaseisoformformation AT nigelmhooper glypican1mediatesbothprionproteinlipidraftassociationanddiseaseisoformformation
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Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.

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