The Role and Regulation of Endosomal GTP Exchange Factors

内体 GTP 交换因子的作用和调节

• 批准号: RGPIN-2022-04573
• 负责人: Conibear, Elizabeth
• 金额: $ 3.5万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760756
• 关键词: Role; Regulation; Endosomal; GTP; Exchange

Every cell is like a busy city: it has to coordinate information flow, clear waste, and move materials to where they are needed. Like cities, cells have a complex internal transportation system that controls traffic. Special machinery ensures that the right type of material is loaded into different transport containers, and delivered to the correct destination. This project focuses on important drivers in the cellular transportation system called "sorting nexins". Many of the traffic signals and pathways present in humans are also found in baker's yeast, a simple single-celled organism. Studying sorting nexins in yeast allows us to use different genome-wide technologies to uncover pathways and machinery on a very large scale and make discoveries that would be difficult or impossible in complex organisms. In fact, an important type of sorting nexin called "retromer" was first discovered in yeast, and many key discoveries about retromer are still being made in this model system. We discovered that a family of activator proteins regulate retromer in yeast. One of these proteins, called "VARP", was also found to be important for retromer function in human cells. This gives us the unparalleled opportunity to use yeast to study VARP and establish exactly how it regulates retromer-like sorting machineries. Our work so far is already generating important insights. The yeast VARP protein that we discovered not only controls the assembly of an entirely new type of sorting nexin, but actually forms an integral part of this machinery. Our proposed research will examine how yeast VARP chooses the specific components that make up this sorting nexin, and how the parts work together to form transport carriers. We will identify how different materials such as proteins are recognized and packaged into these carriers. In addition, we will study the regulatory processes that control how and when this sorting nexin machinery operates in the cell. This research will have a number of important impacts. It will reveal general principles that control the formation and function of transport carriers that regulate the distribution of proteins within the cell, knowledge that can be transferred to the study of human cells. In the long term, it could also have economic benefits for Canada. Yeast cells are used as "mini-factories" to produce different proteins for pharmaceutical and bioprocessing applications, such as the removal of toxins from the environment. Understanding how proteins are transported within the cell can increase the efficiency of these yeast "cell factories" in the production of biopharmaceuticals and industrial enzymes.

每一个细胞都像一座忙碌的城市：它必须协调信息流，清除废物，并将材料运送到需要的地方。像城市一样，细胞有一个复杂的内部交通系统来控制交通。特殊的机械确保正确类型的材料被装载到不同的运输容器中，并被运送到正确的目的地。该项目的重点是细胞运输系统中的重要驱动因素，称为“分类连接蛋白”。许多存在于人类身上的交通信号和路径也存在于面包酵母中，面包酵母是一种简单的单细胞生物。研究酵母中的分类连接蛋白使我们能够使用不同的全基因组技术来大规模地揭示途径和机制，并在复杂的生物体中发现困难或不可能的发现。事实上，一种被称为“retromer”的重要分类连接蛋白最早是在酵母中发现的，关于retromer的许多关键发现仍在这个模型系统中进行。我们发现一个家族的激活蛋白调节酵母中的retromer。其中一种称为“VARP”的蛋白质也被发现对人类细胞中的逆转录功能很重要。这为我们提供了无与伦比的机会，可以使用酵母来研究VARP，并确切地确定它是如何调节类似逆转录酶的分选机器的。 到目前为止，我们的工作已经产生了重要的见解。我们发现的酵母VARP蛋白不仅控制着一种全新的分类连接蛋白的组装，而且实际上形成了这种机器的一个组成部分。我们提出的研究将研究酵母VARP如何选择组成这种分选连接蛋白的特定组分，以及这些组分如何共同作用形成运输载体。我们将确定不同的材料，如蛋白质是如何识别和包装到这些载体。此外，我们还将研究控制这种分类连接蛋白机制在细胞中如何以及何时运作的调控过程。这项研究将产生一些重要影响。它将揭示控制运输载体的形成和功能的一般原则，这些运输载体调节细胞内蛋白质的分布，这些知识可以转移到人类细胞的研究中。从长远来看，这也可能给加拿大带来经济利益。酵母细胞被用作“微型工厂”，生产用于制药和生物加工应用的不同蛋白质，例如从环境中去除毒素。了解蛋白质如何在细胞内运输可以提高这些酵母“细胞工厂”在生物制药和工业酶生产中的效率。