Enhancement of proteasome activity by a small-molecule inhibitor of USP14

Byung Hoon Lee, Min Jae Lee, Soyeon Park, Dong Chan Oh, Suzanne Elsasser, Ping Chung Chen, Carlos Gartner, Nevena Dimova, John Hanna, Steven P. Gygi, Scott M. Wilson, Randall W. King, Daniel Finley

Research output: Contribution to journalArticle

537 Citations (Scopus)

Abstract

Proteasomes, the primary mediators of ubiquitin-protein conjugate degradation, are regulated through complex and poorly understood mechanisms. Here we show that USP14, a proteasome-associated deubiquitinating enzyme, can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in cells. A catalytically inactive variant of USP14 has reduced inhibitory activity, indicating that inhibition is mediated by trimming of the ubiquitin chain on the substrate. A high-throughput screen identified a selective small-molecule inhibitor of the deubiquitinating activity of human USP14. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress.

Original languageEnglish
Pages (from-to)179-184
Number of pages6
JournalNature
Volume467
Issue number7312
DOIs
StatePublished - 9 Sep 2010

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Proteasome Endopeptidase Complex
Ubiquitin
Proteolysis
Human Activities
Neurodegenerative Diseases
Cultured Cells
Oxidative Stress
Proteins

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Lee, B. H., Lee, M. J., Park, S., Oh, D. C., Elsasser, S., Chen, P. C., ... Finley, D. (2010). Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature, 467(7312), 179-184. https://doi.org/10.1038/nature09299
Lee, Byung Hoon ; Lee, Min Jae ; Park, Soyeon ; Oh, Dong Chan ; Elsasser, Suzanne ; Chen, Ping Chung ; Gartner, Carlos ; Dimova, Nevena ; Hanna, John ; Gygi, Steven P. ; Wilson, Scott M. ; King, Randall W. ; Finley, Daniel. / Enhancement of proteasome activity by a small-molecule inhibitor of USP14. In: Nature. 2010 ; Vol. 467, No. 7312. pp. 179-184.
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Lee, BH, Lee, MJ, Park, S, Oh, DC, Elsasser, S, Chen, PC, Gartner, C, Dimova, N, Hanna, J, Gygi, SP, Wilson, SM, King, RW & Finley, D 2010, 'Enhancement of proteasome activity by a small-molecule inhibitor of USP14', Nature, vol. 467, no. 7312, pp. 179-184. https://doi.org/10.1038/nature09299

Enhancement of proteasome activity by a small-molecule inhibitor of USP14. / Lee, Byung Hoon; Lee, Min Jae; Park, Soyeon; Oh, Dong Chan; Elsasser, Suzanne; Chen, Ping Chung; Gartner, Carlos; Dimova, Nevena; Hanna, John; Gygi, Steven P.; Wilson, Scott M.; King, Randall W.; Finley, Daniel.

In: Nature, Vol. 467, No. 7312, 09.09.2010, p. 179-184.

Research output: Contribution to journalArticle

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Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature. 2010 Sep 9;467(7312):179-184. https://doi.org/10.1038/nature09299