Proteasome inhibitors activate autophagy involving inhibition of PI3K-Akt-mTOR pathway as an anti-oxidation defense in human RPE cells.
Proteasome inhibitors activate autophagy involving inhibition of PI3K-Akt-mTOR pathway as an anti-oxidation defense in human RPE cells.
复制标题
蛋白酶体抑制剂激活自噬，涉及抑制 PI3K-Akt-mTOR 通路，作为人 RPE 细胞的抗氧化防御。
DOI：
10.1371/journal.pone.0103364
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wu S
中科院分区：
文献类型：
--
作者：
Tang B;Cai J;Sun L;Li Y;Qu J;Snider BJ;Wu S
两个主要的细胞内蛋白质降解系统，泛素-蛋白酶体系统（UPS）和自噬，在许多生物过程中协同工作，包括发育，凋亡，衰老和对抗氧化损伤。我们在这里报告，在人视网膜色素上皮细胞（RPE）中，ARPE-19细胞，蛋白酶体抑制剂，裂乳蛋白β-内酯（LA）或环氧霉素（Epo），在非致死剂量下，增加了自噬特异性基因Atg 5和Atg 7的蛋白水平，并增强了微管相关蛋白轻链（LC 3）从LC 3-I向其脂质形式LC 3-II的转化，这通过共添加饱和浓度的巴弗洛霉素A1（Baf）而增强。LC 3染色和标记溶酶体共定位检测进一步证实了LA或Epo诱导的自噬通量。LA或Epo降低了ARPE-19细胞中蛋白激酶B（Akt）、磷脂酰肌醇-3-激酶（PI 3 K）的下游靶标和雷帕霉素的哺乳动物靶标（mTOR）的磷酸化;相反，自噬底物p62的诱导变化呈双相模式。在暴露于甲萘醌（VK 3）或4-羟基壬烯醛（4-HNE）的ARPE-19细胞中，自噬抑制剂Baf减弱了低剂量LA和Epo治疗所引起的氧化损伤的减少。在ARPE-19细胞中用siRNA敲低Atg 7降低了LA或Epo对VK 3的保护作用。总体而言，我们的结果表明，低水平的蛋白酶体抑制剂治疗通过抑制PI 3 K-Akt-mTOR通路和激活自噬的途径赋予对氧化损伤的抗性。
The two major intracellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, work collaboratively in many biological processes including development, apoptosis, aging, and countering oxidative injuries. We report here that, in human retinal pigment epithelial cells (RPE), ARPE-19 cells, proteasome inhibitors, clasto-lactacystinβ-lactone (LA) or epoxomicin (Epo), at non-lethal doses, increased the protein levels of autophagy-specific genes Atg5 and Atg7 and enhanced the conversion of microtubule-associated protein light chain (LC3) from LC3-I to its lipidative form, LC3-II, which was enhanced by co-addition of the saturated concentration of Bafilomycin A1 (Baf). Detection of co-localization for LC3 staining and labeled-lysosome further confirmed autophagic flux induced by LA or Epo. LA or Epo reduced the phosphorylation of the protein kinase B (Akt), a downstream target of phosphatidylinositol-3-kinases (PI3K), and mammalian target of rapamycin (mTOR) in ARPE-19 cells; by contrast, the induced changes of autophagy substrate, p62, showed biphasic pattern. The autophagy inhibitor, Baf, attenuated the reduction in oxidative injury conferred by treatment with low doses of LA and Epo in ARPE-19 cells exposed to menadione (VK3) or 4-hydroxynonenal (4-HNE). Knockdown of Atg7 with siRNA in ARPE-19 cells reduced the protective effects of LA or Epo against VK3. Overall, our results suggest that treatment with low levels of proteasome inhibitors confers resistance to oxidative injury by a pathway involving inhibition of the PI3K-Akt-mTOR pathway and activation of autophagy.
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蛋白酶体抑制剂对钙网蛋白/钙连接蛋白质量控制系统成分的减少及其在帕金森病啮齿动物模型中的相关性
影响因子：
4.2
作者：
Kuang, Xiu-Li;Liu, Fang;Chen, Huifang;Li, Yiping;Liu, Yimei;Xiao, Jian;Shan, Ge;Li, Mingjie;Snider, B. Joy;Qu, Jia;Barger, Steven W.;Wu, Shengzhou
通讯作者：
Wu, Shengzhou
影响因子：
30.8
作者：
Gal, A;Li, Y;Vollrath, D
通讯作者：
Vollrath, D
影响因子：
30.8
作者：
Ravikumar, B;Vacher, C;Rubinsztein, DC
通讯作者：
Rubinsztein, DC
影响因子：
4.8
作者：
Lu, CB;Chan, SL;Mattson, MP
通讯作者：
Mattson, MP
DOI：
10.1073/pnas.222551899
发表时间：
2002-11-12
影响因子：
11.1
作者：
Crabb, JW;Miyagi, M;Hollyfield, JG
通讯作者：
Hollyfield, JG