Elucidating the conserved role of palmitoylation in autophagy.

阐明棕榈酰化在自噬中的保守作用。

• 批准号: RGPIN-2019-04617
• 负责人: Martin, Dale
• 金额: $ 2.7万
• 依托单位: University of Waterloo
• 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=745804
• 关键词: Elucidating; conserved; role; palmitoylation; autophagy.

The cell is the smallest unit that makes up organs and tissues and it is important to understand the mechanisms that are required for cell survival. One crucial mechanism for cell survival is known as autophagy, which simply means "self-eating." It refers to how cells degrade non-functional components that might become toxic to the cell. Autophagy can also recycle these materials for energy during starvation. As such, autophagy is sometimes referred to as the trash bin or garburator of the cell. When non-functional components build up they can become toxic, much like an overflowing garburator. Therefore, it is important to understand how autophagy functions at the molecular level in the cell, particularly within the nervous system where neurons are more susceptible to cell death when autophagy is disrupted. Autophagy is present in all organisms that contain a nucleus, a compartment storing DNA. This includes essentially anything that is not bacteria or virus - from yeast to humans. Therefore, understanding autophagy even in the simplest organism, like yeast, can have applications in humans. Autophagy is dependent on proteins to properly localise within the cell to specialised compartments known as organelles. In autophagy, an organelle known as the autophagosome encompasses the toxic molecules and delivers them to the lysosome, an acidic organelle, to be degraded, like in a garburator. One way that proteins are targeted to different organelles is by adding small modifications to proteins, like a fat or lipid. One of these lipid modifications of protein is referred to as palmitoylation. Palmitoylation is unique among fatty modifications because it can be also be removed from proteins, making it dynamic. So, palmitoylated proteins can be released from organelles by removing the palmitoylation modification on the protein. The goal of my research program is to determine the molecular basis of the cellular signaling process of palmitoylation in autophagy and how it is conserved from yeast to mammals by pursuing the following aims. Aim 1 - Identify the proteins/enzymes that mediate palmitoylation during autophagy. Aim 2 - Determine how palmitoylation regulates autophagy. Aim 3 - Characterise how fat in the affects palmitoylation in autophagy. Students and trainees will gain valuable skills in biochemistry and cell biology including unique palmitoylation assays that can be performed in any biological tissue as well as high resolution cell imaging techniques. This research will provide new insights into the crucial mechanism of how proteins are targeted to membranes in autophagy. Knowledge from simple organisms will be applied to more complex ones to determine how autophagy is regulated in the nervous system. Ultimately, it will also provide details of how diet may regulate these important pathways.

细胞是构成器官和组织的最小单位，了解细胞生存所需的机制是很重要的。细胞存活的一个关键机制是自噬，意思就是“自我吞噬”。它指的是细胞如何降解可能对细胞产生毒性的非功能性成分。自噬还可以在饥饿期间回收这些物质的能量。因此，自噬有时被称为细胞的垃圾桶或加气器。当非功能部件堆积起来时，它们可能会变得有毒，就像一个溢出的加油器。因此，重要的是要了解自噬是如何在细胞的分子水平上发挥作用的，特别是在神经系统中，当自噬被破坏时，神经元更容易受到细胞死亡的影响。自噬存在于所有含有细胞核的有机体中，细胞核是储存DNA的隔间。这基本上包括任何不是细菌或病毒的东西--从酵母到人类。因此，了解自噬即使是在最简单的有机体中，如酵母，也可以在人类身上得到应用。自噬依赖于蛋白质在细胞内适当地定位到被称为细胞器的特殊隔间。在自噬中，一个被称为自噬小体的细胞器包裹着有毒分子，并将它们输送到溶酶体，这是一种酸性细胞器，像在加气器中一样被降解。将蛋白质定位于不同细胞器的一种方法是对蛋白质进行微小的修饰，如脂肪或脂质。蛋白质的这些脂质修饰之一被称为棕榈酰化。棕榈酰化在脂肪修饰中是独一无二的，因为它也可以从蛋白质中移除，使其具有活力。因此，棕榈酰化的蛋白质可以通过去除蛋白质上的棕榈酰化修饰而从细胞器中释放出来。我的研究计划的目标是通过追求以下目标来确定自噬中棕榈酰化的细胞信号过程的分子基础，以及如何将其从酵母保存到哺乳动物。目的1-确定在自噬过程中介导棕榈酰化的蛋白质/酶。目的2-确定棕榈酰化如何调节自噬。目的3-描述自噬中脂肪对棕榈酰化的影响。学生和受训人员将获得生物化学和细胞生物学方面的宝贵技能，包括可在任何生物组织中进行的独特棕榈酰化分析以及高分辨率细胞成像技术。这项研究将为自噬中蛋白质如何定位于膜的关键机制提供新的见解。来自简单生物体的知识将被应用于更复杂的生物体，以确定神经系统中自噬是如何调节的。最终，它还将提供饮食如何调节这些重要途径的细节。