SNARE-mediated membrane fusion involved in autophagosome biogenesis

SNARE 介导的膜融合参与自噬体生物发生

• 批准号: 10582100
• 负责人: Jiajie Diao
• 金额: $ 15.31万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582100
• 关键词: Autophagocytosis; Autophagosome; Biogenesis; Development; Diabetes Mellitus; Disease; Functional disorder; Future; Human; Investigation; Longevity; Malignant Neoplasms; Mediating; Membrane Fusion; Membrane Fusion Activity; Modification; Molecular; Morphology; Neurodegenerative Disorders; Nuclear Receptors; Pathway interactions; Process; Proteins; Quality Control; Role; SNAP receptor; Stress; Therapeutic; base; drug development; human disease; novel therapeutic intervention; receptor binding; reconstitution; response; wasting

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.

项目摘要 自噬是细胞废物回收的重要分解代谢途径。自噬功能障碍 与细胞质量控制、对压力的反应、发育、寿命和 人类的一系列传染病和其他疾病，包括癌症，神经退行性疾病， 和糖尿病膜融合是自噬体生物发生的关键过程。的 自噬膜融合的确切分子机制仍远未清楚，因此是一个主要的问题 调查的主题。由于膜融合活动可以作为空间和时间的开关， 调节人类疾病中的自噬通量，由于其失调，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至关重要。因此，我们认为， 研究膜融合的调节机制将为开发新的 治疗策略，以控制自噬的活性。根据我们的初步发现， 我们假设自噬SNARE的形态和修饰状态是重要的， 用于介导自噬体生物发生中涉及的膜融合，而这一过程是 由辅助蛋白调节，包括核受体结合因子2和Atg 9。进一步 系统研究了SNARE介导的膜融合在自噬体成熟中的作用， 起始对于阐明详细分子机制至关重要， 预付款。此外，寻找新的融合子和重建早期自噬体的尝试， 生物合成是一个重要的扩展，这对未来的药物开发也至关重要。

项目成果

Prefused lysosomes cluster on autophagosomes regulated by VAMP8.

• DOI: 10.1038/s41419-021-04243-0
• 发表时间: 2021-10-13
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Chen Q;Hao M;Wang L;Li L;Chen Y;Shao X;Tian Z;Pfuetzner RA;Zhong Q;Brunger AT;Guan JL;Diao J
• 通讯作者: Diao J

Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts.

• DOI: 10.1038/s41467-022-31970-5
• 发表时间: 2022-07-25
• 期刊: Nature communications
• 影响因子: 16.6

Molecular structures and function of the autophagosome-lysosome fusion machinery.

• DOI: 10.1080/27694127.2024.2305594
• 发表时间: 2024-02
• 期刊: Autophagy reports
• 作者: Jiajie Diao;Calvin K Yip;Qing Zhong

VAMP8 phosphorylation regulates lysosome dynamics during autophagy.

• DOI: 10.1080/27694127.2022.2031378
• 发表时间: 2022
• 期刊: Autophagy reports

Monitoring lysosomal acidity.

监测溶酶体酸度。

• DOI: 10.1038/s41589-023-01348-9
• 发表时间: 2023
• 期刊: Nature chemical biology
• 影响因子: 14.8
• 作者: Qiu,Kangqiang;Tian,Zhiqi;Diao,Jiajie
• 通讯作者: Diao,Jiajie