571159-05-2Relevant articles and documents
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,Catarina Silva,Seong, Changhyun,Elsasser, Suzanne,Hatle, Ketki M.,Gahman, Timothy C.,Gygi, Steven P.,Haggarty, Stephen J.,Gan, Li,King, Randall W.,Finley, Daniel
, p. 19209 - 19225 (2017/12/01)
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.
COMPOSITIONS AND METHODS FOR ENHANCING PROTEASOME ACTIVITY
-
Page/Page column 71, (2011/08/21)
Proteinopathies result from the proteasome not acting efficiently enough to eliminate harmful proteins and prevent the formation of the pathogenic aggregates. As described herein, inhibition of proteasome-associated deubiquitinase Usp 14 results in increased proteasome efficiency. The present invention therefore provides novel compositions and methods for inhibition of Uspl4, enhancement of proteasome activity and treatment of proteinopathies.
