Cited 2 time in webofscience Cited 4 time in scopus

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

Title
An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons
Authors
Boselli, MonicaLee, Byung HoonRobert, JessicaPrado, Miguel A.Min, Sang-WonCheng, ChialinSilva, M. CatarinaSeong, ChanghyunElsasser, SuzanneHatle, Ketki M.Gahman, Timothy C.Gygi, Steven P.Haggarty, Stephen J.Gan, LiKing, Randall W.Finley, Daniel
DGIST Authors
Lee, Byung Hoon
Issue Date
2017-11
Citation
Journal of Biological Chemistry, 292(47), 19209-19225
Type
Article
Article Type
Article
Keywords
UBIQUITIN-SPECIFIC PROTEASESMALL-MOLECULE INHIBITORALZHEIMERS-DISEASEFRONTOTEMPORAL DEMENTIA26S PROTEASOMEMEDIATED NEURODEGENERATIONTRANSGENIC MICEATAXIA MICEDEGRADATIONAUTOPHAGY
ISSN
0021-9258
Abstract
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. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
URI
http://hdl.handle.net/20.500.11750/5638
DOI
10.1074/jbc.M117.815126
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Related Researcher
  • Author Lee, Byung Hoon Lab of Protein Homeostasis and Drug Discovery
  • Research Interests Ubiquitin-proteasome system; Protein homeostasis; Small-molecule chemical screening and drug discovery in human disease
Files:
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Collection:
Department of New BiologyLab of Protein Homeostasis and Drug Discovery1. Journal Articles


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