Ambra1调控细胞自噬的分子机制研究

项目名称： Ambra1调控细胞自噬的分子机制研究

项目编号： No.31300645

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 王硕

作者单位： 中国科学院生物物理研究所

项目金额： 22万元

中文摘要： 自噬是细胞在受到外界刺激或是某些特定生理过程中，细胞降解自身的细胞器和冗余的蛋白质，从而维持细胞正常代谢的一种细胞生物学过程。自噬因其在胚胎发育和疾病发生等过程中发挥着重要作用，近几年来成为研究热点。Beclin1-Vps34复合物对于自噬的进行非常重要，Beclin1活性的丧失会抑制自噬，并且促进肿瘤的发生。Ambra1是自噬调控过程中的重要分子之一，但Ambra1调控自噬的分子机理还不清楚。我们在研究中发现在自噬过程中，Beclin1能进行的K63位修饰的泛素化，而这种类型的泛素化修饰能够增强Beclin1-Vps34复合物的活性。同时也我们发现Ambra1敲低以后，Belcin1的泛素化水平受到抑制。本课题希望进一步证实Ambra1动态调控Beclin1泛素化的分子机制，寻找Ambra1调控Beclin1泛素化的复合物，揭示Ambra1调控自噬的分子机制。

中文关键词： Ambra1；Beclin1；细胞自噬；泛素化；RNF2

英文摘要： Autophagy is a physiological process that cells degrade organelles and redundant proteins during stimulation in order to maintain their normal metabolism. During autophagy induction, double-membrane vesicles called autophagosomes are produced to sequester intracellular cargos and fused with lysosomes to form autolysosomes for subsequent degradation. Because of its essential roles in embryonic development and disease process, autophagy becomes an important issue these years. Beclin1 is an essential protein for autophagy. Deficiency of Beclin1 leads to abrogation of autophagy. Beclin1 is also a tumor suppressor by increasing autophagy level. Low Beclin1 activity is responsible for tumorigenesis. Ambra1 is one of the most important proteins for autophagy. Ambra1 is a WD repeat domain-containing protein that activates Beclin1-dependent autophagy. Ambra1 deficiency leads to early embryonic lethality, and autophagy defects. Ambra1 interacts with Beclin1 and promotes the association of Beclin1 with Vps34, which is essential for autophagy initiation. However, the molecular mechanism of Ambra1-regulated autophagy is unknown. In our study, we found that Beclin1 is ubiquitinated during autophagy. Ubiquitination of Beclin1 promotes the interaction between Beclin1 and Vps34, and also increases the activity of Vps34. We foun

英文关键词： Ambra1；Beclin1；autophagy；ubiquitination；RNF2