Enhancement of proteasome activity by a small-molecule inhibitor of USP14.
Enhancement of proteasome activity by a small-molecule inhibitor of USP14.
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蛋白酶体是泛素-蛋白质结合物降解的主要介体，通过复杂而鲜为人知的机制进行调节。在这里，我们证明了Usp14，一种蛋白酶体相关的去泛素化酶，在体内和体外都可以抑制泛素-蛋白质结合物的降解。Usp14的一个催化失活变体降低了抑制活性，表明抑制是通过修剪底物上的泛素链介导的。高通量筛选确定了人Usp14去泛素化活性的选择性小分子抑制物。用这种化合物处理培养细胞可以促进几种蛋白酶体底物的降解，这些底物与神经退行性疾病有关。抑制USP14可加速氧化蛋白的降解，增强对氧化应激的抗性。通过抑制Usp14来增强蛋白酶体的活性可能为降低蛋白毒性应激下细胞中异常蛋白的水平提供了一种策略。
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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DOI：
10.1523/jneurosci.2635-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen PC;Qin LN;Li XM;Walters BJ;Wilson JA;Mei L;Wilson SM
通讯作者：
Wilson SM
影响因子：
16.8
作者：
Kleijnen, Maurits F.;Roelofs, Jeroen;Finley, Daniel
通讯作者：
Finley, Daniel
影响因子：
5.3
作者：
Crimmins, Stephen;Jin, Youngam;Wilson, Scott M.
通讯作者：
Wilson, Scott M.
影响因子：
4.8
作者：
Jacobson, Andrew D.;Zhang, Nan-Yan;Liu, Chang-Wei
通讯作者：
Liu, Chang-Wei
影响因子：
16.6
作者：
Finley D
通讯作者：
Finley D