Activation of Autophagy of Aggregation-prone Ubiquitinated Proteins by Timosaponin A-III
Activation of Autophagy of Aggregation-prone Ubiquitinated Proteins by Timosaponin A-III
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DOI：
10.1074/jbc.m110.202531
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发表时间：
2011-09-09
影响因子：
4.8
通讯作者：
Che, Chi-Ming
中科院分区：
文献类型：
--
作者：
Lok, Chun-Nam;Sy, Lai-King;Che, Chi-Ming
自噬的化学调节剂为检查自噬过程提供了有用的药理学工具，并且还可能导致用于疾病的新治疗剂，其中控制细胞螯合和降解能力是有益的。我们已经确定，知母皂苷A-III（TAIII），一种药用皂苷，据报道表现出抗癌特性和改善脑功能，是一个显着的自噬激活剂。在这项工作中，TAIII诱导的自噬的显著特征和功能作用进行了研究。在TAIII处理的细胞中，自噬通量与自噬体形成增加和转化为自溶酶体诱导与雷帕霉素活性的哺乳动物靶点的抑制和胞质游离钙的升高相关。TAIII诱导的自噬与雷帕霉素的常规诱导不同，表现出大的自噬空泡，其似乎含有大量的内体膜和多泡体。此外，TAIII刺激胆固醇的生物合成，胆固醇被掺入自噬泡膜。TAIII诱导的自噬空泡捕获泛素化蛋白，并且在蛋白酶体抑制的细胞中，TAIII促进易于聚集的泛素化蛋白的自噬。我们的研究表明，TAIII诱导了一种独特的自噬形式，其药理作用之一可能是通过自噬清除积累的泛素化蛋白聚集体来增强细胞质量控制能力。
Chemical modulators of autophagy provide useful pharmacological tools for examination of autophagic processes, and also may lead to new therapeutic agents for diseases in which control of cellular sequestration and degradation capacity are beneficial. We have identified that timosaponin A-III (TAIII), a medicinal saponin reported to exhibit anticancer properties and improve brain function, is a pronounced activator of autophagy. In this work, the salient features and functional role of TAIII-induced autophagy were investigated. In TAIII-treated cells, autophagic flux with increased formation of autophagosomes and conversion into autolysosomes is induced in association with inhibition of mammalian target of rapamycin activity and elevation of cytosolic free calcium. The TAIII-induced autophagy is distinct from conventional induction by rapamycin, exhibiting large autophagic vacuoles that appear to contain significant contents of endosomal membranes and multivesicular bodies. Furthermore, TAIII stimulates biosynthesis of cholesterol, which is incorporated to the autophagic vacuole membranes. The TAIII-induced autophagic vacuoles capture ubiquitinated proteins, and in proteasome-inhibited cells TAIII promotes autophagy of aggregation-prone ubiquitinated proteins. Our studies demonstrate that TAIII induced a distinct form of autophagy, and one of its pharmacological actions is likely to enhance the cellular quality control capacity via autophagic clearance of otherwise accumulated ubiquitinated protein aggregates.