Δ12-prostaglandin J2 inhibits the ubiquitin hydrolase UCH-L1 and elicits ubiquitin-protein aggregation without proteasome inhibition
Δ12-prostaglandin J2 inhibits the ubiquitin hydrolase UCH-L1 and elicits ubiquitin-protein aggregation without proteasome inhibition
复制标题
DOI：
10.1016/j.bbrc.2004.05.098
复制
发表时间：
2004-07-09
影响因子：
3.1
通讯作者：
Figueiredo-Pereira, ME
中科院分区：
文献类型：
--
作者：
Li, ZM;Melandri, F;Figueiredo-Pereira, ME
为了研究将炎症与神经退行性变联系起来的分子机制，我们用炎性介质-处理神经元培养物。PGA 1、D2、J2和Delta 12-PGJ 2，但不是PGE 2，降低了神经元细胞的活力并提高了神经元细胞中泛素化蛋白的水平。PGJ 2及其代谢产物Delta 12-PGJ 2是测试的四种神经毒性PG中诱导两种效应的最有效的。为了解决这些药物导致泛素化蛋白积累的机制，我们测试了它们对神经元泛素水解酶UCH-L1和UCH-L3以及蛋白酶体活性的影响。值得注意的是，Delta 12-PGJ 2抑制UCH-L1（Ki类似于3.5 μ M）和UCH-L3（Ki类似于8.1 μ M）的活性，而不影响蛋白酶体活性。在Delta 12-PGJ 2处理的细胞中检测到含有泛素化蛋白的细胞内聚集体，表明这些聚集体可以独立于蛋白酶体抑制而形成。总之，泛素水解酶活性的损害，如由Delta 12-PGJ 2引发的，可能是与泛素化蛋白质积累和炎症相关的神经变性的重要贡献者。(C)2004年爱思唯尔公司All rights reserved.
To investigate molecular mechanisms linking inflammation with neurodegeneration, we treated neuronal cultures with prostaglandins (PGs), which are mediators of inflammation. PGA1, D2, J2, and Delta12-PGJ2, but not PGE2, reduced the viability and raised the levels of ubiquitinated proteins in the neuronal cells. PGJ2 and its metabolite, Delta12-PGJ2, were the most potent of the four neurotoxic PGs tested in inducing both effects. To address the mechanism by which these agents lead to the accumulation of ubiquitinated proteins, we tested their effects on neuronal ubiquitin hydrolases UCH-L1 and UCH-L3 as well as on proteasome activity. Notably, Delta12-PGJ2 inhibited the activities of UCH-L1 (K-i similar to 3.5 muM) and UCH-L3 (K-i similar to 8.1 muM) without affecting proteasome activity. Intracellular aggregates containing ubiquitinated proteins were detected in Delta12-PGJ2-treated cells, indicating that these aggregates can form independently of proteasome inhibition. In conclusion, impairment of ubiquitin hydrolase activity, such as triggered by Delta12-PGJ2, may be an important contributor to neurodegeneration associated with accumulation of ubiquitinated proteins and inflammation. (C) 2004 Elsevier Inc. All rights reserved.