Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.

Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。

基本信息

  • 批准号:
    10704918
  • 负责人:
  • 金额:
    $ 2.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-01 至 2026-04-30
  • 项目状态:
    未结题

项目摘要

Abstract In the three major intracellular trafficking pathways–exocytosis, endocytosis and autophagy–proteins and membranes are secreted, internalized or shuttled for degradation, respectively. These pathways are regulated by the conserved Ypt/Rab GTPases that when activated by nucleotide exchangers (GEFs), recruit their effectors to membranes. These effectors are machinery components that mediate vesicular transport steps, from vesicle formation, through motility and targeting, to fusion. I have worked in the Ypt/Rab field since its inception and contributed to the formulation of principles that underlie their mode of action. These include ideas that they function in “GTPase modules”, which contain GEF/s, a GTPase, and effector/s, to organize pathway- or step-specific membrane microdomains. While mechanisms underlying Ypt/Rab function are currently known, questions regarding pathway and step coordination remain open. We propose that Ypt/Rab GTPases coordinate intracellular trafficking at three levels: Coordination of multiple pathways, integration of transport steps into whole pathways, and coordination of vesicular transport sub-steps of individual transport steps. The proposed research relies on our recent findings using yeast as a model system, and we will continue using yeast due to its smaller proteome that results in a much smaller interactome, which is important for exploring the following coordination issues: Multiple pathways coordination: I propose that Ypt/Rabs coordinate autophagy with secretion and endocytosis at two intersections. In the first, Ypt1/Rab1 is required for the beginning of secretion and autophagy in the context of two different GTPase modules. In the second intersection, merging of endocytosis and late autophagy is regulated by a shared Vps21/Rab5 GTPase module. Here, we will determine whether cells prioritize certain pathways under different environmental conditions and how such a priority is promoted. Integration of transport steps: Here, we will address two major questions: First, how do Ypts regulate the beginning of a pathway, especially when a single GTPase functions in the context of two different modules? Second, what are the specific mechanisms by which Ypts coordinate early and late steps in secretion and autophagy? Coordination of vesicular transport sub-steps: We will explore late steps of the secretory and autophagy pathways, for which members of the GTPase modules are known, and ask how effectors that function sequentially are recruited. We will use classical and molecular genetics combined with cell biology and biochemistry approaches to address these questions. An efficient and well-coordinated network of cellular trafficking pathways is important for all the systems of the human body, and even a minor defect can result in a severe disease. Ypt/Rabs in general were implicated in a spectrum of acquired and inherited diseases, and those we study were associated with cancer and neurodegeneration. Finally, we recently showed the value of yeast modeling in understanding how a conserved protein variant causes a neurodevelopmental disorder.
摘要 在三种主要的细胞内运输途径-胞吐,胞吞和自噬-蛋白质和 膜分别被分泌、内化或穿梭降解。这些途径受到调节 通过保守的Ypt/Rab GTP酶,当被核苷酸交换剂(GEF)激活时, 膜效应器。这些效应器是介导囊泡转运步骤的机械组件, 从囊泡的形成,到运动和靶向,再到融合。我一直在YPT/拉布领域工作,因为它 该组织成立于1998年,并为制定其行动方式的基本原则作出了贡献。其中包括思想 它们在包含GEF、GTdR和效应子的“GTdR模块”中起作用,以组织通路- 或阶特异性膜微区。虽然目前已知Ypt/Rab功能的潜在机制, 关于途径和步骤协调的问题仍然是开放的。我们建议Ypt/Rab GTP酶 在三个水平协调细胞内运输:多途径协调,运输整合 进入整个途径的步骤,以及单个运输步骤的囊泡运输子步骤的协调。 拟议的研究依赖于我们最近的发现,使用酵母作为模型系统,我们将继续使用 酵母由于其较小的蛋白质组,导致更小的相互作用组,这对于探索 以下协调问题:多途径协调:我建议Ypt/Rabs协调 自噬与分泌和内吞作用在两个交叉点。在第一种情况下,需要Ypt 1/Rab 1, 在两个不同的GTdR模块的背景下开始分泌和自噬。在第二 内吞和晚期自噬的交叉、合并受共享Vps 21/Rab 5 GTdR调控 module.在这里,我们将确定细胞是否在不同的环境下优先考虑某些途径。 条件以及如何促进这一优先事项。运输步骤的整合:在这里,我们将解决两个主要问题 问题:首先,Ypts如何调节通路的开始,特别是当单个GTpts起作用时 在两个不同的模块中?第二,Ypts协调的具体机制是什么 分泌和自噬的早期和晚期步骤?囊泡转运子步骤的协调:我们将探索 分泌和自噬途径的后期步骤,其中已知GTd 3模块的成员, 并询问如何招募顺序发挥作用的效应器。我们将使用经典和分子遗传学 结合细胞生物学和生物化学方法来解决这些问题。 一个有效和协调良好的细胞运输途径网络对于所有系统都是重要的。 对人体来说,即使是一个微小的缺陷也可能导致严重的疾病。Ypt/Rabs一般都与一个 获得性和遗传性疾病谱,我们研究的那些与癌症有关, 神经变性最后,我们最近展示了酵母建模在理解 保守的蛋白质变体导致神经发育障碍。

项目成果

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Nava Segev其他文献

Nava Segev的其他文献

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{{ truncateString('Nava Segev', 18)}}的其他基金

Aberrant P-bodies accumulation and clearance in yeast and human cells.
酵母和人体细胞中异常 P 体的积累和清除。
  • 批准号:
    10551880
  • 财政年份:
    2022
  • 资助金额:
    $ 2.56万
  • 项目类别:
Aberrant P-bodies accumulation and clearance in yeast and human cells.
酵母和人体细胞中异常 P 体的积累和清除。
  • 批准号:
    10390634
  • 财政年份:
    2022
  • 资助金额:
    $ 2.56万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10832932
  • 财政年份:
    2021
  • 资助金额:
    $ 2.56万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10581959
  • 财政年份:
    2021
  • 资助金额:
    $ 2.56万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10798944
  • 财政年份:
    2021
  • 资助金额:
    $ 2.56万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10615724
  • 财政年份:
    2021
  • 资助金额:
    $ 2.56万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10197424
  • 财政年份:
    2021
  • 资助金额:
    $ 2.56万
  • 项目类别:
Coordination of intracellular trafficking pathways by Ypt/Rab GTPases and their GEFs.
Ypt/Rab GTPases 及其 GEF 协调细胞内运输途径。
  • 批准号:
    10399615
  • 财政年份:
    2021
  • 资助金额:
    $ 2.56万
  • 项目类别:
The role of Rab1 GTPase and its activators in selective autophagy and neurodegenerative disease
Rab1 GTPase 及其激活剂在选择性自噬和神经退行性疾病中的作用
  • 批准号:
    9225579
  • 财政年份:
    2016
  • 资助金额:
    $ 2.56万
  • 项目类别:
ROLE OF YPT GTPASES IN INTRACELLULAR TRAFFICKING
YPT GTASE 在细胞内贩运中的作用
  • 批准号:
    7957793
  • 财政年份:
    2009
  • 资助金额:
    $ 2.56万
  • 项目类别:
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