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Regulation of autophagy induction by the Vps34 complex: structural and functional studies.

Vps34 复合物对自噬诱导的调节：结构和功能研究。

基本信息

批准号：
BB/K019155/1
负责人：
Nicholas Ktistakis
金额：
$ 40.2万
依托单位：
Babraham Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK019155%2F1
关键词：
Regulation autophagy induction Vps34 complex

项目摘要

This work will determine the mechanism by which the lipid kinase Vps34 and its lipid product PI3P regulate autophagy. Autophagy (from the Greek self-eating) is a way for cells to generate nutrients from their own material during times of starvation. The pathway of autophagy is very important for the health of an organism for several reasons. Autophagy underpins the normal physiology of all cell types, and is a critical contributor to life-span extension. Cellular components that are damaged become substrates for autophagy and are efficiently eliminated. This leads to a periodic clean-up of the cell interior and allows for regeneration of important proteins and organelles. Of note, when autophagy is suppressed cells exhibit signs of oxidative damage because their dysfunctional mitochondria cannot be removed and continue to produce reactive oxygen species. Similarly, suppression of autophagy contributes in a significant way to the build-up of mutant aggregate-prone proteins (which are normally substrates of autophagic degradation) that cause neuro-degenerative disorders. Autophagy is also critical for the neo natal period: animals that cannot mount autophagy die soon after birth because they cannot generate nutrients from their own resources during a period where they do not obtain nutrients from the outside.The pathway of autophagy starts when a novel double membrane vesicle called autophagosome is formed in the cell interior. These autophagosomes (which can be hundreds in number at any one time) enclose cellular material and deliver it to a degradative organelle called lysosome for digestion. There is currently high interest in finding ways to enhance or suppress autophagy for various health-related reasons and the best place to start is to undesratnd how autophagosomes are formed.Our previous work has shown that one of the signals for formation of autophagosomes is the synthesis of a lipid called PI3P by the activity of the Vps34 enzyme. This results in the formation of a series of intermediate structures that eventually give rise to an autophagosome. However exactly how this happens and how the intermediate structures eventually lead to an autophagosome is a mystery and will be tackled by our proposed work.We will combine expertise in cell biology and structural biology in order to find the structure of the Vps34 comlex that regulates the start of autophagy, and we will use biochemistry and microscopy to describe in detail the pathway that leads from PI3P to autophagosome formation.

这项工作将确定脂质激酶Vps34及其脂质产物PI3P调节自噬的机制。自噬（来自希腊语自我进食）是细胞在饥饿期间从自身物质中产生营养的一种方式。自噬途径对生物体的健康非常重要，原因有几个。自噬支持所有细胞类型的正常生理学，并且是延长寿命的关键贡献者。受损的细胞成分成为自噬的底物并被有效地消除。这导致细胞内部的定期清理，并允许重要蛋白质和细胞器的再生。值得注意的是，当自噬被抑制时，细胞表现出氧化损伤的迹象，因为它们功能失调的线粒体不能被去除并继续产生活性氧。类似地，自噬的抑制以显著的方式有助于导致神经退行性疾病的突变聚集倾向蛋白（其通常是自噬降解的底物）的积累。自噬在新生纳塔尔时期也是至关重要的：不能进行自噬的动物在出生后不久就会死亡，因为它们在无法从外部获得营养的时期无法从自己的资源中产生营养。自噬途径始于细胞内部形成一种称为自噬体的新型双膜囊泡。这些自噬体（在任何时候都可以有数百个）包围细胞物质，并将其运送到称为溶酶体的降解细胞器进行消化。目前，人们对寻找增强或抑制自噬的方法有很高的兴趣，因为各种健康相关的原因，最好的起点是了解自噬体是如何形成的。我们以前的工作表明，自噬体形成的信号之一是通过Vps34酶的活性合成一种称为PI3P的脂质。这导致一系列中间结构的形成，最终产生自噬体。我们将联合收割机结合细胞生物学和结构生物学的专业知识，以找到调节自噬开始的Vps34复合体的结构，并将使用生物化学和显微镜详细描述从PI3 P到自噬体形成的途径。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ultrastructural insights into pathogen clearance by autophagy.

DOI：
10.1111/tra.12723
发表时间：
2020-04
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
0
作者：
Kishi-Itakura C;Ktistakis NT;Buss F
通讯作者：
Buss F

Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles.

DOI：
10.1038/ncomms12420
发表时间：
2016-08-11
期刊：
Nature communications
影响因子：
16.6
作者：
Karanasios E;Walker SA;Okkenhaug H;Manifava M;Hummel E;Zimmermann H;Ahmed Q;Domart MC;Collinson L;Ktistakis NT
通讯作者：
Ktistakis NT

The dynamics of mitochondrial autophagy at the initiation stage.

DOI：
10.1042/bst20210272
发表时间：
2021-11-01
期刊：
Biochemical Society transactions
影响因子：
3.9
作者：
Ktistakis NT
通讯作者：
Ktistakis NT

Imaging autophagy.

成像自噬。

DOI：
10.1002/0471142956.cy1234s69
发表时间：
2014
期刊：
Current protocols in cytometry
影响因子：
0
作者：
Karanasios E
通讯作者：
Karanasios E

Sorting nexin 5 mediates virus-induced autophagy and immunity.

排序Nexin 5介导病毒诱导的自噬和免疫力。

DOI：
10.1038/s41586-020-03056-z
发表时间：
2021-01
期刊：
Nature
影响因子：
64.8
作者：
Dong X;Yang Y;Zou Z;Zhao Y;Ci B;Zhong L;Bhave M;Wang L;Kuo YC;Zang X;Zhong R;Aguilera ER;Richardson RB;Simonetti B;Schoggins JW;Pfeiffer JK;Yu L;Zhang X;Xie Y;Schmid SL;Xiao G;Gleeson PA;Ktistakis NT;Cullen PJ;Xavier RJ;Levine B
通讯作者：
Levine B