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J Biol Chem. 2017 Nov 24;292(47):19209-19225. doi: 10.1074/jbc.M117.815126. Epub 2017 Sep 26.

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

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From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
the Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, 42988 Daegu, Korea.
the Department of Neurology, Gladstone Institute of Neurological Diseases, University of California, San Francisco, California 94158.
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
Regeneron Pharmaceuticals, Tarrytown, New York 10591, and.
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, California 92093.
From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,
From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115,


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.


IU1; IU1-47; neurodegenerative disease; proteasome; small molecule; tauopathy; ubiquitin

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