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An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons

  • Author(s): Boselli, M
  • Lee, BH
  • Robert, J
  • Prado, MA
  • Min, SW
  • Cheng, C
  • Catarina Silva, M
  • Seong, C
  • Elsasser, S
  • Hatle, KM
  • Gahman, TC
  • Gygi, SP
  • Haggarty, SJ
  • Gan, L
  • King, RW
  • Finley, D
  • et al.

Published Web Location

http://www.jbc.org/content/292/47/19209.long
No data is associated with this publication.
Creative Commons Attribution-NonCommercial 4.0 International Public License
Abstract

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. The ubiquitin-proteasome system (UPS) is responsible for most selective protein degradation in eukaryotes and regulates numerous cellular processes, including cell cycle control and protein quality control. A component of this system, the deubiquitinating enzyme USP14, associates with the proteasome where it can rescue substrates from degradation by removal of the ubiquitin tag. We previously found that a small-molecule inhibitor of USP14, known as IU1, can increase the rate of degradation of a subset of proteasome substrates. We report here the synthesis and characterization of 87 variants of IU1, which resulted in the identification of a 10-fold more potent USP14 inhibitor that retains specificity for USP14. The capacity of this compound, IU1-47, to enhance protein degradation in cells was tested using as a reporter the microtubule-associated protein tau, which has been implicated in many neurodegenerative diseases. Using primary neuronal cultures, IU1-47 was found to accelerate the rate of degradation of wild-type tau, the pathological tau mutants P301L and P301S, and the A152T tau variant. We also report that a specific residue in tau, lysine 174, is critical for the IU1-47–mediated tau degradation by the proteasome. Finally, we show that IU1-47 stimulates autophagic flux in primary neurons. In summary, these findings provide a powerful research tool for investigating the complex biology of USP14.

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