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An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons
- An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons
- Boselli, Monica; Lee, Byung Hoon; Robert, Jessica; Prado, Miguel A.; Min, Sang-Won; Cheng, Chialin; Silva, M. Catarina; Seong, Changhyun; Elsasser, Suzanne; Hatle, Ketki M.; Gahman, Timothy C.; Gygi, Steven P.; Haggarty, Stephen J.; Gan, Li; King, Randall W.; Finley, Daniel
- DGIST Authors
- Lee, Byung Hoon
- Issue Date
- Journal of Biological Chemistry, 292(47), 19209-19225
- Article Type
- UBIQUITIN-SPECIFIC PROTEASE; SMALL-MOLECULE INHIBITOR; ALZHEIMERS-DISEASE; FRONTOTEMPORAL DEMENTIA; 26S PROTEASOME; MEDIATED NEURODEGENERATION; TRANSGENIC MICE; ATAXIA MICE; DEGRADATION; AUTOPHAGY
- 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.
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Related Researcher
Lee, Byung Hoon
Lab of Protein Homeostasis and Drug Discovery
Ubiquitin-proteasome system; Protein homeostasis; Small-molecule chemical screening and drug discovery in human disease
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