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MBC in Press, published online ahead of print June 30, 2004
Mol. Biol. Cell 10.1091/mbc.E03-05-0271

A more recent version of this article appeared on September 1, 2004
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Submitted on May 2, 2003
Revised on June 4, 2004
Accepted on June 22, 2004

PrPC Association with Lipid Rafts in the Early Secretory Pathway Stabilizes Its Cellular Conformation

Daniela Sarnataro*{dagger}, Vincenza Campana*{dagger}{ddagger}, Simona Paladino*, Mariano Stornaiuolo{sect}, Lucio Nitsch*, and Chiara Zurzolo*{ddagger}||

*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; {ddagger}Unité de Trafic Membranaire et Pathogénèse, Institut Pasteur, 75724 Paris Cedex 15, France; {sect}Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy

Monitoring Editor: Keith Mostov

The pathological conversion of PrPC into the PrPSc 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 PrPC to rafts during its biosynthesis. We found that PrPC 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 PrPC with cholesterol-enriched rafts facilitates its correct folding and reinforce the hypothesis that cholesterol and sphingolipids have different roles in PrP metabolism.

{dagger}These authors contributed equally to this work.

||Corresponding author. E-mail: zurzolo{at}pasteur.fr




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