在“泛素-蛋白酶体”系统（该系统通过降解受损的或多余的蛋白而在真核细胞中扮演一个重要角色）中，注定要被破坏的基质被“泛素链”共价修饰，随后又被蛋白酶体降解。现在，一个新的调控机制已在人体细胞中被识别出来，蛋白酶体活性通过这个机制来被“泛素链”的长度调控。“去泛素化”酶Usp14可以通过修剪“泛素链”来抑制与泛素结合在一起的基质的降解。
而且，研究人员还用一种化学筛选方法识别了Usp14的一个小分子抑制因子，用这种化合物对哺乳动物细胞进行处理，会导致包括氧化蛋白和致病有毒蛋白在内的各种不同基质的更多清除。因此，蛋白酶体活性的刺激也许为降低细胞中有毒蛋白水平提供了一个策略。（生物谷Bioon.com）
生物谷推荐英文摘要：
Nature doi:10.1038/nature09299
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& Daniel Finley
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.
