摘要
背景:损坏或错误折叠的蛋白在视网膜色素上皮(RPE)细胞的积累在老年性黄斑变性(AMD)中被认为是影响视网膜色素上皮功能障碍。泛素蛋白酶体通路(UPP)和自噬溶酶体途径(ALP)对错误折叠或损坏的蛋白质的清除是两个主要的蛋白水解系统的 目的:旨在探讨这两个系统怎样交流与视网膜色素上皮细胞在消除细胞内错误折叠和受损的蛋白质中怎样相互协调。 方法:体外培养的ARPE-19细胞被分别饲养蛋白酶体抑制剂MG132和溶酶体剂氯喹(CQ)。泛素化蛋白LC3-I、LC3-II,LAMP1和P62的水平和细胞分布进行免疫印迹和免疫荧光分析。使用Suc-LLVY-AMC为底物测定蛋白酶体活性。 结果:泛素化蛋白聚集水平是在视网膜色素上皮细胞MG132治疗后明显增加。MG132处理后的细胞LC3-I,LC3-II LAMP1水平增加。在MG132处理后γ-微管蛋白和P62的水平也增加,这表明泛素蛋白酶体通路上调自噬溶酶体途径的抑制作用。使用溶酶体剂氯喹抑制溶酶体活性也增加了高质量的泛素结合物水平、LC3-II和p62。此外,蛋白酶体的活性受到损害后会导致长期的溶酶体抑制 结论:这些数据表明,泛素蛋白酶体通路和自噬溶酶体途径是相互关联的,自噬溶酶体途径功能障碍也会导致泛素蛋白酶体通路功能障碍和对消除错误折叠和其他形式损坏的蛋白质的能力严重损害。
关键词: 泛素;蛋白酶体;自噬;溶酶体;蛋白质聚集体。
Current Molecular Medicine
Title:Crosstalk Between the Autophagy-Lysosome Pathway and the Ubiquitin-Proteasome Pathway in Retinal Pigment Epithelial Cells
Volume: 16 Issue: 5
Author(s): J. Zhan, J. He, Y. Zhou, M. Wu, Y. Liu, F. Shang, X. Zhang
Affiliation:
关键词: 泛素;蛋白酶体;自噬;溶酶体;蛋白质聚集体。
摘要: Background: The accumulation of damaged or misfolded proteins in retinal pigment epithelial (RPE) cells was considered a contributing factor for RPE dysfunction in age-related macular degeneration (AMD). The ubiquitinproteasome pathway (UPP) and the autophagy-lysosome pathway (ALP) are the two major proteolytic systems for clearance of misfolded or damaged proteins.
Objective: The aim is to investigate how these two systems communicate and coordinate with each other in RPE cells for eliminating intracellular misfolded and damaged proteins.
Methods: Cultured ARPE-19 cells were treated with proteasome inhibitor MG132 and lysosomotropic agent chloroquine (CQ), respectively. The levels and cellular distributions of ubiquitinated proteins, LC3-I, LC3-II, LAMP1 and p62 were analyzed by Western blotting and immunofluorescence. Proteasome activity was determined using Suc-LLVY-AMC as a substrate.
Results: The level of ubiquitinated protein aggregations was significantly increased after the treatment of MG132 in RPE cells. The levels of LC3-I, LC3-II and LAMP1 increased in MG132 treated cells. The levels of γ-tubulin and p62 also increased in MG132 treated cells, suggesting that inhibition of the UPP up-regulates autophagy-lysosome pathway. Inhibition of lysosomal activity with CQ also increased the levels of high mass ubiquitin conjugates, LC3-II and p62. In addition, proteasome activity was compromised upon prolonged lysosomal inhibition.
Conclusions: These data indicate that the UPP and the ALP are interrelated and that dysfunction of the ALP would also result in dysfunction of the UPP and severely compromise the capacity of eliminating misfolded and other forms of damaged proteins.
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Cite this article as:
J. Zhan, J. He, Y. Zhou, M. Wu, Y. Liu, F. Shang, X. Zhang , Crosstalk Between the Autophagy-Lysosome Pathway and the Ubiquitin-Proteasome Pathway in Retinal Pigment Epithelial Cells, Current Molecular Medicine 2016; 16 (5) . https://dx.doi.org/10.2174/1566524016666160429121606
DOI https://dx.doi.org/10.2174/1566524016666160429121606 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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