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

By Byung-Hoon Lee, Min Jae Lee, Soyeon Park, D. Oh, S. Elsasser, Ping Chen, C. Gartner, Nevena V. Dimova, John Hanna, Steven P. Gygi and 3 more. Nature, 2010

930 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/335c5c0605949bbc7bf9aa27ec24a8d84cefefdb

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Citations in the corpus

The role of ubiquitination in tumorigenesis and targeted drug discovery (2020, background): “(450)) and enhance proteasome function by blocking the access of the C-terminus of Ub to the active site of USP14.(451) Currently, many new screening methods have been developed and used to select small-molecule inhibitors and compounds for DUB.”
PubChem's BioAssay Database (2011, methodology): “…assay were deposited by the Laboratory of Environmental Genomics at the Carolina Center for Computational toxicology, University of North Carolina at Chapel Hill (http://comptox.unc.edu/); and a USP14 inhibitor assay was deposited by the Finley and King Labs at the Harvard Medical School (9).”
Pathways of cellular proteostasis in aging and disease (2018, background): “The UPS mainly serves to target individual proteins to the proteasome, whereas the autophagy system clears larger aggregates or membrane-associated proteins (Menzies et al., 2015; Ciechanover and Kwon, 2017).”
In vivo aspects of protein folding and quality control (2016, background): “Finally, activating the UPS or inducing autophagy with smallmolecule compounds can enhance degradation and reduce aggregate load (184, 185).”
The Logic of the 26S Proteasome. (2017, positive): “This kinetic competition mechanism was first recognized by Finley and colleagues (Crosas et al., 2006) and provided the rationale for their development of small molecule Usp14 inhibitors to enhance substrate degradation (Lee et al., 2010).”
Oxidative stress in neurodegenerative diseases (2012, background): “Since the proteasome represents the major proteolytic machinery for the removal of oxidized and misfolded protein [60] , inhibition of the proteasome or decreasing proteasomal activity will result in an accumulation of abnormal proteins [61] .”
Molecular chaperones in protein folding and proteostasis (2011, neutral): “Likewise, recently identified proteasome activator”
The hallmarks of aging. (2013, background): “Likewise, the enhancement of proteasome activity by deubiquitylase inhibitors or proteasome activators accelerates the clearance of toxic proteins in human cultured cells (Lee et al., 2010) and extends replicative lifespan in yeast (Kruegel et al., 2011).”
Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13 (2011, neutral): “Interestingly, the treatment of spautin-1 also reduced the levels of USP10 and USP13, but not USP14, a DUB involved in regulating proteasome function (Lee et al., 2010), or Rubicon, a negative regulator of type III PI3 kinase”