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

• DOI: 10.1074/jbc.m117.815126
• Publication Date: 2017-10-03T00:25:18Z
• Authors: 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; Li Gan; Randall W. King; Daniel Finley
• Keywords: Deubiquitinating enzyme; Protein Degradation; Tau protein

The ubiquitin-proteasome system (UPS) is responsible for most selective protein degradation in eukaryotes and regulates numerous cellular processes, including cell cycle control quality control. A component of this system, the deubiquitinating enzyme USP14, associates with proteasome where it can rescue substrates from by removal ubiquitin tag. We previously found that a small-molecule inhibitor known as IU1, increase rate subset substrates. report here synthesis characterization 87 variants which resulted identification 10-fold more potent USP14 retains specificity USP14. capacity compound, IU1-47, to enhance cells was tested using reporter microtubule-associated tau, has been implicated many neurodegenerative diseases. Using primary neuronal cultures, IU1-47 accelerate wild-type pathological tau mutants P301L P301S, A152T variant. also specific residue lysine 174, critical IU1-47-mediated proteasome. Finally, we show stimulates autophagic flux neurons. In summary, these findings provide powerful research tool investigating complex biology