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© The Rockefeller University Press, 0021-9525/2003/8/703 $5.00
The Journal of Cell Biology, Volume 162, Number 4, 703-717

Trafficking of prion proteins through a caveolae-mediated endosomal pathway

¹ Section of Tumor Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
² Department of Molecular Cell Biology, Free University, 1081 BT Amsterdam, Netherlands
³ Department of Cell Biology, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, Netherlands
⁴ Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143
⁵ Department of Neurology, University of California, San Francisco, CA 94143
⁶ Department of Pathology, University of California, San Francisco, CA 94143
⁷ Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143
⁸ Department of Immunology, Scripps Research Institute, La Jolla, CA 92037

Address correspondence to Peter J. Peters, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121-H4, 1066 CX Amsterdam, The Netherlands. Tel.: 31-20-512 2989. Fax: 31-20-617-2029. email: p.peters{at}nki.nl

To understand the posttranslational conversion of the cellular prion protein (PrP^C) to its pathologic conformation, it is important to define the intracellular trafficking pathway of PrP^C within the endomembrane system. We studied the localization and internalization of PrP^C in CHO cells using cryoimmunogold electron microscopy. At steady state, PrP^C 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 PrP^C 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 PrP^C-containing caveolae were not directed to the ER and Golgi complex. Uptake of caveolae and degradation of PrP^C 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 PrP^C conversion.

Key Words: prion; caveolae; endosomal pathway; electron microscopy; cryoimmunogold

M. Vey's present address is Aventis Behring GmbH, Marburg, Germany.

Abbreviations used in this paper: CLD, caveolae-like domain; GPI, glycosylphosphatidyl inositol; PIPLC, phosphatidylinositol-specific phospholipase C; PrP^C, cellular isoform of the prion protein; PrP^Sc, disease-causing isoform of the prion protein.

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