Methylarginine Dynamics in Cellular Processes

细胞过程中的甲基精氨酸动力学

• 批准号: RGPIN-2020-04227
• 负责人: Frankel, Adam
• 金额: $ 2.33万
• 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=762004
• 关键词: Methylarginine; Dynamics; Cellular; Processes

Organisms depend on nutrients to grow and proliferate, but the availability of such resources can be limiting at times. This situation represents a stress on a cellular level. The response to this type of stress is studied in the unicellular organism Saccharomyces cerevisiae, commonly referred to as baker's yeast. Research has emerged that cells experiencing nutrient deprivation undergo significant changes to ensure their long-term survival through the winter of their discontent. Under these conditions, cells break down and recycle their components within a vacuole compartment in a process called autophagy, which is necessary for extending the lifespan of the organism. The amino acid arginine is stored in the vacuole and used as one of many protein building blocks. My laboratory studies a methyltransferase enzyme family that attaches small carbon units to the ends of arginine within proteins. This simple modification exerts profound cellular effects by altering molecular interactions. The long-term objective of my program of research is to determine how methyltransferase activity affects a broad set of cellular processes, and specifically for this NSERC proposal in the short-term, how the methylated arginine metabolites from autophagy affect cell survival and lifespan. In our investigation into the yeast response to nutrient deprivation, we found significant changes on methylated arginine outside of cells that was dependent on which gene was deleted. We plan to show that this amino acid efflux is a product of autophagy, and that preventing methylated arginine efflux from yeast under stress compromises important processes required for long-term survival. We will search for and characterize new arginine methyltransferases in yeast whose gene deletions impact the efflux of specific methylarginine species. The broad range of state-of-the-art, cell-based, and biochemical methods required to achieve the goals of the research program will provide analytical, communication, and time management skills for HQP that will make them competitive within Canada's natural sciences community and productive in its knowledge-driven economy. I intend on training a diverse group of three qualified HQP recruited with an awareness around equity and inclusiveness with this NSERC award. Together, our findings will have a profound effect on our understanding of how methylarginine metabolism affects cell survival in yeast for a global network of researchers studying arginine methyltransferases, autophagy, and aging.

生物体依赖营养物质生长和繁殖，但这些资源的可用性有时可能是有限的。这种情况代表了细胞水平上的压力。在单细胞生物酿酒酵母（Saccharomyces cerevisiae）中研究了对这种类型的应激的反应，通常称为面包酵母。研究表明，经历营养缺乏的细胞会发生重大变化，以确保它们在不满的冬天长期存活。在这些条件下，细胞在一个称为自噬的过程中分解并回收其成分，这是延长生物体寿命所必需的。氨基酸精氨酸储存在液泡中，并用作许多蛋白质构建块之一。我的实验室研究一个甲基转移酶家族，该家族将小碳单元连接到蛋白质内精氨酸的末端。这种简单的修饰通过改变分子间的相互作用而产生深远的细胞效应。我的研究计划的长期目标是确定甲基转移酶活性如何影响一系列广泛的细胞过程，特别是对于NSERC的短期建议，自噬的甲基化精氨酸代谢物如何影响细胞存活和寿命。在我们对酵母对营养剥夺的反应的研究中，我们发现细胞外甲基化精氨酸的显着变化取决于哪个基因被删除。我们计划证明这种氨基酸流出是自噬的产物，并且在压力下阻止甲基化精氨酸从酵母中流出会损害长期生存所需的重要过程。我们将在酵母中寻找和鉴定新的精氨酸甲基转移酶，其基因缺失会影响特定甲基精氨酸种类的外排。实现研究计划目标所需的各种最先进的，基于细胞的和生物化学方法将为HQP提供分析，沟通和时间管理技能，使其在加拿大自然科学界具有竞争力，并在其知识驱动的经济中富有成效。我打算培训一个由三名合格的HQP组成的多元化小组，他们在NSERC奖项的公平性和包容性方面具有意识。总之，我们的研究结果将对我们理解甲基精氨酸代谢如何影响酵母细胞存活产生深远的影响，这是一个研究精氨酸甲基转移酶，自噬和衰老的全球研究人员网络。