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Vol. 15, Issue 9, 4031-4042, September 2004

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PrP^C Association with Lipid Rafts in the Early Secretory Pathway Stabilizes Its Cellular Conformation

Daniela Sarnataro ^* , Vincenza Campana ^*  , Simona Paladino ^* , Mariano Stornaiuolo , Lucio Nitsch ^*, and Chiara Zurzolo ^*  ||

^* Dipartimento di Biologia e Patologia Cellulare e Molecolare, Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy; Unité de Trafic Membranaire et Pathogénèse, Institut Pasteur, 75724 Paris Cedex 15, France; and Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy

Submitted May 2, 2003; Revised June 4, 2004; Accepted June 22, 2004
Monitoring Editor: Keith Mostov

The pathological conversion of cellular prion protein (PrP^C) into the scrapie prion protein (PrP^Sc) isoform appears to have a central role in the pathogenesis of transmissible spongiform encephalopathies. However, the identity of the intracellular compartment where this conversion occurs is unknown. Several lines of evidence indicate that detergent-resistant membrane domains (DRMs or rafts) could be involved in this process. We have characterized the association of PrP^C to rafts during its biosynthesis. We found that PrP^C associates with rafts already as an immature precursor in the endoplasmic reticulum. Interestingly, compared with the mature protein, the immature diglycosylated form has a different susceptibility to cholesterol depletion vs. sphingolipid depletion, suggesting that the two forms associate with different lipid domains. We also found that cholesterol depletion, which affects raft-association of the immature protein, slows down protein maturation and leads to protein misfolding. On the contrary, sphingolipid depletion does not have any effect on the kinetics of protein maturation or on the conformation of the protein. These data indicate that the early association of PrP^C with cholesterol-enriched rafts facilitates its correct folding and reinforce the hypothesis that cholesterol and sphingolipids have different roles in PrP metabolism.

Abbreviations used: BiP, binding protein; CD, methyl--cyclodextrin; CLT, calreticulin; CNX, calnexin; DRMs, detergent-resistant membrane domains; Endo-H, endoglycosidase-H; ER, endoplasmic reticulum; FB1, fumonisin B1; FRT, Fischer rat thyroid; GPI, glycosylphosphatidylinositol; Mev, mevinolin; PK, proteinase K; PDI, protein disulfide isomerase; PrP^C, cellular prion protein; PrP^Sc, scrapie prion protein; TGN, trans-Golgi network; TNE, Tris/NaCl/EDTA; TSEs, transmissible spongiform encephalopathies; TX-100, Triton X-100.

Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.

These authors contributed equally to this work.

^|| Corresponding author. E-mail addresses: zurzolo{at}unina.it; zurzolo{at}pasteur.fr.

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