title: Trafficking of prion proteins through a caveolae-mediated endosomal pathway.
abstract: To understand the posttranslational conversion of the cellular prion protein (PrPC) to its pathologic conformation, it is important to define the intracellular trafficking pathway of PrPC within the endomembrane system. We studied the localization and internalization of PrPC in CHO cells using cryoimmunogold electron microscopy. At steady state, PrPC was enriched in caveolae both at the TGN and plasma membrane and in interconnecting chains of endocytic caveolae. Protein A-gold particles bound specifically to PrPC on live cells. These complexes were delivered via caveolae to the pericentriolar region and via nonclassical, caveolae-containing early endocytic structures to late endosomes/lysosomes, thereby bypassing the internalization pathway mediated by clathrin-coated vesicles. Endocytosed PrPC-containing caveolae were not directed to the ER and Golgi complex. Uptake of caveolae and degradation of PrPC was slow and sensitive to filipin. This caveolae-dependent endocytic pathway was not observed for several other glycosylphosphatidyl inositol (GPI)-anchored proteins. We propose that this nonclassical endocytic pathway is likely to determine the subcellular location of PrPC conversion.
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121-H4, 1066 CX Amsterdam, The Netherlands. p.peters@nki.nl
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Peters
authors.forename: Alexander
authors.initials: A
authors.lastname: Mironov
authors.forename: David
authors.initials: D
authors.lastname: Peretz
authors.forename: Elly
authors.initials: E
authors.lastname: van Donselaar
authors.forename: Estelle
authors.initials: E
authors.lastname: Leclerc
authors.forename: Susanne
authors.initials: S
authors.lastname: Erpel
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Williamson
authors.forename: Martin
authors.initials: M
authors.lastname: Vey
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D016466:CHO Cells; D021941:Caveolae / Q000378:metabolism* / Q000648:ultrastructure; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000235:genetics; D006224:Cricetinae; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D017979:Gold Colloid / Q000378:metabolism; D008854:Microscopy, Electron; D011328:Prions / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011990:Receptors, Transferrin / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D051242:Caveolin 1; D022461:Caveolins; D017979:Gold Colloid; D011328:Prions; D011990:Receptors, Transferrin; C070001:protein AG-gold complex