Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry

• Published in: The EMBO journal Vol. 30; no. 15; pp. 3065 - 3077
• Main Authors: Deriziotis, Pelagia, André, Ralph, Smith, David M, Goold, Rob, Kinghorn, Kerri J, Kristiansen, Mark, Nathan, James A, Rosenzweig, Rina, Krutauz, Dasha, Glickman, Michael H, Collinge, John, Goldberg, Alfred L, Tabrizi, Sarah J
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 03.08.2011; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; Humans; Immunoprecipitation; Mice; Mice, Transgenic; Models, Molecular; Molecular biology; neuroscience; Neurosciences; Peptides; prion; Prions; proteasome; Proteasome Inhibitors; Protein Binding; Protein Interaction Mapping; Proteins; PrP; PrPSc Proteins - metabolism; UPS
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.224

Prion diseases are associated with the conversion of cellular prion protein (PrPC) to toxic β‐sheet isoforms (PrPSc), which are reported to inhibit the ubiquitin‐proteasome system (UPS). Accordingly, UPS substrates accumulate in prion‐infected mouse brains, suggesting impairment of the 26S proteasome. A direct interaction between its 20S core particle and PrP isoforms was demonstrated by immunoprecipitation. β‐PrP aggregates associated with the 20S particle, but did not impede binding of the PA26 complex, suggesting that the aggregates do not bind to its ends. Aggregated β‐PrP reduced the 20S proteasome's basal peptidase activity, and the enhanced activity induced by C‐terminal peptides from the 19S ATPases or by the 19S regulator itself, including when stimulated by polyubiquitin conjugates. However, the 20S proteasome was not inhibited when the gate in the α‐ring was open due to a truncation mutation or by association with PA26/PA28. These PrP aggregates inhibit by stabilising the closed conformation of the substrate entry channel. A similar inhibition of substrate entry into the proteasome may occur in other neurodegenerative diseases where misfolded β‐sheet‐rich proteins accumulate. Prion protein aggregates disrupt proteasome activity. Here, mechanistic insight into this phenomenon is provided: β‐PrP binds the 20S proteasome and inhibits gate opening.