在“泛素-蛋白酶體”系統(tǒng)（該系統(tǒng)通過降解受損的或多余的蛋白而在真核細胞中扮演一個重要角色）中，注定要被破壞的基質被“泛素鏈”共價修飾,，隨后又被蛋白酶體降解。現在,，一個新的調控機制已在人體細胞中被識別出來，蛋白酶體活性通過這個機制來被“泛素鏈”的長度調控,。“去泛素化”酶Usp14可以通過修剪“泛素鏈”來抑制與泛素結合在一起的基質的降解,。
而且，研究人員還用一種化學篩選方法識別了Usp14的一個小分子抑制因子,，用這種化合物對哺乳動物細胞進行處理,，會導致包括氧化蛋白和致病有毒蛋白在內的各種不同基質的更多清除。因此，蛋白酶體活性的刺激也許為降低細胞中有毒蛋白水平提供了一個策略,。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
