title: Enhancement of proteasome activity by a small-molecule inhibitor of USP14.
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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
authors.forename: Min Jae
authors.initials: MJ
authors.lastname: Lee
authors.forename: Soyeon
authors.initials: S
authors.lastname: Park
authors.forename: Dong-Chan
authors.initials: DC
authors.lastname: Oh
authors.forename: Suzanne
authors.initials: S
authors.lastname: Elsasser
authors.forename: Ping-Chung
authors.initials: PC
authors.lastname: Chen
authors.forename: Carlos
authors.initials: C
authors.lastname: Gartner
authors.forename: Nevena
authors.initials: N
authors.lastname: Dimova
authors.forename: John
authors.initials: J
authors.lastname: Hanna
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wilson
authors.forename: Randall W
authors.initials: RW
authors.lastname: King
authors.forename: Daniel
authors.initials: D
authors.lastname: Finley
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors*; D054875:Ubiquitination
chemical_list: D011506:Proteins; C509299:USP14 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex