Stimulation of Akt poly-ubiquitination and proteasomal degradation in P388D1 cells by 7-ketocholesterol and 25-hydroxycholesterol.
Stimulation of Akt poly-ubiquitination and proteasomal degradation in P388D1 cells by 7-ketocholesterol and 25-hydroxycholesterol.
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DOI：
10.1016/j.abb.2009.05.004
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发表时间：
2009-07-01
影响因子：
3.9
通讯作者：
Thewke DP
中科院分区：
文献类型：
--
作者：
Liu J;Netherland C;Pickle T;Sinensky MS;Thewke DP
Akt在保护巨噬细胞免受某些氧固醇诱导的凋亡中起作用。先前，我们观察到用25-羟基胆固醇（25-OH）或7-酮基胆固醇（7-KC）处理后，P388 D1单核细胞/巨噬细胞中Akt的降解增强。在本报告中，我们研究了泛素蛋白酶体途径在这一过程中的作用。我们发现，25-OH或7-KC治疗的结果在聚泛素化Akt的积累，这是增强与蛋白酶体抑制剂MG-132的共同治疗的效果。通过添加Gly-Ala重复序列（GAr）（已知阻断蛋白质的泛素依赖性靶向蛋白酶体的结构域）修饰Akt，产生了对由25-OH或7-KC诱导的翻转具有抗性的嵌合蛋白，并提供了对由这些氧固醇诱导的细胞凋亡的保护。这些结果揭示了氧化固醇调节巨噬细胞中Akt的新方面;氧化固醇刺激的Akt的多聚泛素化和蛋白酶体途径的降解。
Akt plays a role in protecting macrophages from apoptosis induced by some oxysterols Previously we observed enhanced degradation of Akt in P388D1 moncocyte/macrophages following treatment with 25-hydroxycholesterol (25-OH) or 7-ketocholesterol (7-KC). In the present report we examine the role of the ubiquitin proteasomal pathway in this process. We show that treatment with 25-OH or 7-KC results in the accumulation of poly-ubiquitinated Akt, an effect that is enhanced by co-treatment with the proteasome inhibitor MG-132. Modification of Akt by the addition of a Gly-Ala repeat (GAr), a domain known to block ubiquitin-dependent targeting of proteins to the proteasome, resulted in a chimeric protein that is resistant to turn-over induced by 25-OH or 7-KC and provides protection from apoptosis induced by these oxysterols. These results uncover a new aspect of oxysterol regulation of Akt in macrophages; oxysterol-stimulated poly-ubiquitination of Akt and degradation by the proteasomal pathway.
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影响因子：
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作者：
Freeman-Anderson, Natalie E.;Pickle, Theresa G.;Thewke, Douglas P.
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