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 () and Daniel Finley ()
Additional contact information
Byung-Hoon Lee: Harvard Medical School
Min Jae Lee: Harvard Medical School
Soyeon Park: Harvard Medical School
Dong-Chan Oh: Harvard Medical School
Suzanne Elsasser: Harvard Medical School
Ping-Chung Chen: Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama at Birmingham
Carlos Gartner: Harvard Medical School
Nevena Dimova: Harvard Medical School
John Hanna: Harvard Medical School
Steven P. Gygi: Harvard Medical School
Scott M. Wilson: Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama at Birmingham
Randall W. King: Harvard Medical School
Daniel Finley: Harvard Medical School

Nature, 2010, vol. 467, issue 7312, 179-184

Abstract: 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.

Date: 2010
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/nature09299 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:467:y:2010:i:7312:d:10.1038_nature09299

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature09299

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().