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

TitleAn inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons.
Publication TypeJournal Article
Year of Publication2017
AuthorsBoselli M, Lee B-H, Robert J, Prado MA, Min S-W, Cheng C, M Silva C, Seong C, Elsasser S, Hatle KM, Gahman TC, Gygi SP, Haggarty SJ, Gan L, King RW, Finley D
JournalJ Biol Chem
Volume292
Issue47
Pagination19209-19225
Date Published2017 11 24
ISSN1083-351X
KeywordsAnimals, Cells, Cultured, Cytoplasm, Embryo, Mammalian, Enzyme Inhibitors, Fibroblasts, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Proteasome Endopeptidase Complex, Proteolysis, Pyrroles, Rats, Sprague-Dawley, tau Proteins, Ubiquitin, Ubiquitin Thiolesterase, Ubiquitination
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.

DOI10.1074/jbc.M117.815126
Alternate JournalJ. Biol. Chem.
PubMed ID28972160
PubMed Central IDPMC5702663
Grant ListR01 GM066492 / GM / NIGMS NIH HHS / United States
R01 GM043601 / GM / NIGMS NIH HHS / United States
R01 GM095526 / GM / NIGMS NIH HHS / United States
R37 GM043601 / GM / NIGMS NIH HHS / United States
R01 AG054214 / AG / NIA NIH HHS / United States
R01 GM067945 / GM / NIGMS NIH HHS / United States