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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.

Author information

1
From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
2
the Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, 42988 Daegu, Korea.
3
the Department of Neurology, Gladstone Institute of Neurological Diseases, University of California, San Francisco, California 94158.
4
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
5
Regeneron Pharmaceuticals, Tarrytown, New York 10591, and.
6
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, California 92093.
7
From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, randy_king@hms.harvard.edu.
8
From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, daniel_finley@hms.harvard.edu.

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.

KEYWORDS:

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

PMID:
28972160
PMCID:
PMC5702663
DOI:
10.1074/jbc.M117.815126
[Indexed for MEDLINE]
Free PMC Article

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