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

Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

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

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References (65)

Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
DOI
10.1038/emboj.2011.224
pmid
21743439
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

The EMBO Journal – Wiley

Published: Mar 3, 2011

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