SNARE-mediated membrane fusion involved in autophagosome biogenesis

项目总结 自噬是细胞废物循环利用的一条关键的分解代谢途径。自噬功能障碍 与细胞质量控制、对压力的反应、发育、寿命和一系列 人类的传染病和其他疾病，包括癌症、神经退行性疾病和糖尿病。 膜融合是自噬小体生物发生的关键过程。确切的分子 自噬细胞膜融合的机制尚不清楚，因此是一个重要的研究课题。 由于膜融合活性可以作为时空调节自噬通量的开关 在人类疾病中，由于其调节失调，解剖融合机制对于理解 自噬在特定疾病背景下的确切作用。因此，研究其调控机制是十分必要的 膜融合将为开发新的治疗策略提供机会，以控制 自噬活性。根据我们的初步发现，我们假设形态和 自噬陷阱的修饰状态对介导膜融合具有重要意义 自噬小体的生物发生，而这个过程是由包括核在内的辅助蛋白调节的 受体结合因子2和ATG9。对SNARE介导膜作用的进一步系统研究 自噬体成熟和启动中的融合对于阐明详细的分子机制是至关重要的， 可以提供治疗方面的进展。此外，试图寻找新的融合体并重建 早期自噬生物发生是一个重要的扩展，这对未来的药物也是必不可少的 发展。

PROJECT SUMMARY Autophagy is a crucial catabolic pathway by which cellular waste is recycled. Autophagic dysfunction has been implicated in cellular quality control, responses to stress, development, lifespan, and a range of infectious and other diseases in humans, including cancer, neurodegenerative diseases, and diabetes. Membrane fusion is a critical process involved in autophagosome biogenesis. The exact molecular mechanism of autophagic membrane fusion remains far from clear and thus a major topic of investigation. Since membrane fusion activity could act as a switch to spatially and temporally regulate the autophagic flux in human diseases due to its dysregulation, dissecting the fusion machinery is essential to understanding the exact roles of autophagy in specific disease contexts. Therefore, studying the regulatory mechanism of membrane fusion will provide the opportunity to develop new therapeutic strategies in order to control activity of autophagy. Based on our preliminary findings, we hypothesize that the morphology and modification status of autophagic SNAREs are important for mediating membrane fusion involved in autophagosome biogenesis, while this process is regulated by accessory proteins including nuclear receptor binding factor 2 and Atg9. Further systematical studies on the role of SNARE-mediated membrane fusion in autophagosome maturation and initiation are critical to elucidate detailed molecular mechanisms, which could offer therapeutic advances. Moreover, an attempt to find new fusogens and reconstitute the early autophagosome biogenesis is an important expansion, which is also essential for future drug development.