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Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of Usp14

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, in vivo and in vitro....

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Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939003/
https://www.ncbi.nlm.nih.gov/pubmed/20829789
http://dx.doi.org/10.1038/nature09299
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author 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
author_facet 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
author_sort Lee, Byung-Hoon
collection PubMed
description 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, in vivo and in vitro. A catalytically inactive variant of Usp14 has reduced inhibitory activity, suggesting 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.
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spelling pubmed-29390032011-03-09 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 Nature Article 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, in vivo and in vitro. A catalytically inactive variant of Usp14 has reduced inhibitory activity, suggesting 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. 2010-09-09 /pmc/articles/PMC2939003/ /pubmed/20829789 http://dx.doi.org/10.1038/nature09299 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
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
title Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of Usp14
title_full Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of Usp14
title_fullStr Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of Usp14
title_full_unstemmed Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of Usp14
title_short Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of Usp14
title_sort enhancement of proteasome activity by a small-molecule inhibitor of usp14
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939003/
https://www.ncbi.nlm.nih.gov/pubmed/20829789
http://dx.doi.org/10.1038/nature09299
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