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An Inhibitor of the Proteasomal Deubiquitinating Enzyme USP14 Induces Tau Elimination in Cultured Neurons

Monica Boselli, Byung-Hoon Lee, Jessica Robert, Miguel A Prado, Sang-Won Min, Chialin Cheng, M Catarina Silva, Changhyun Seong, Suzanne Elsasser, Ketki M Hatle, Timothy C Gahman, Steven P Gygi, Stephen J Haggarty, etc.

J Biol Chem. 2017 Nov 24;292(47):19209-19225.

PMID: 28972160

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.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
AP314245335 IU1 IU1 314245-33-5 Price
IAR42410930 USP14 Inhibitor, IU1 USP14 Inhibitor, IU1 Price
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