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

Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 09/2010; 467(7312):179-84. DOI: 10.1038/nature09299
Source: PubMed


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.

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    • "Heterotypic K11-PolyUb Conjugates Facilitate Proteasomal Degradation Preferentially to Homotypic K11-PolyUb Chains Proteasome-associated DUBs disassemble Ub chains and can regulate the rate of protein degradation by the 26S (Lee et al., 2010; Peth et al., 2009). As homotypic K11-polyUb conjugates did not bind strongly to the 26S, they should not be able to stimulate degradation by the proteasome; but, it remains unclear whether they can still be targeted by DUBs for disassembly . "
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    • "It would also appear that USP14 is functionally redundant in mammalian cells since knock down produced no discernible effects on proteasome structure or polyubiquitin levels (Koulich et al., 2008). Consistently, the recently developed IU1, a small molecule USP14 inhibitor reduces chain trimming and stimulates the proteasomal degradation of several reporter substrates (Lee et al., 2010). Although non-essential for general cell viability, USP14 does appear to be important for cell survival under certain conditions including metabolic stress and neuronal development (Chen et al., 2009; Chernova et al., 2003; Walters et al., 2008). "
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    • "This DUB is a member of the UCH sub-family and is also known as UCH37. Unlike PSMD14, UCHL5 is not a constitutive subunit of the proteasome but associates with it by binding to the Ub receptor Adrm1 on the 19S subunit (Lee et al., 2010a,b). The proposed role for this DUB at the proteasome is one of poly-Ub chain trimming by hydrolyzing Ub chains at their distal end and releasing mono-Ub for re-utilization (Yao et al., 2006). "
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