Molecular mechanisms that match lysosome function to cellular demand

项目总结/摘要 溶酶体作为大分子降解的主要场所，在细胞的降解能力中发挥核心作用。 细胞感知并响应细胞内营养物质可用性的变化。相反，细胞内 营养素如氨基酸调节溶酶体的性质，包括它们的生物发生、酸化、信号传导 功能和亚细胞位置。定义允许这种协调的分子机制， 溶酶体功能与营养物质的可利用性对于阐明溶酶体内稳态是如何维持的至关重要， 健康和疾病。该项目的重点是由C9 orf 72，SMCR 8和C9 orf 72组成的异源三聚体蛋白质复合物。 WDR 41。我们对这种蛋白质复合物的兴趣源于我们的发现， 氨基酸剥夺，并且是溶酶体的降解功能以及它们的能力所必需的， 支持mTORC 1响应于急性暴露于氨基酸活化。因此，我们提出的研究 试图：1）阐明细胞耦合氨基酸可用性变化的机制 C9 orf 72-SMCR 8-WDR 41向溶酶体的募集。2)定义C9 orf 72的直接溶酶体靶点- SMCR8-WDR 41。3)确定这一整体途径如何整合到溶酶体的维持中 体内平衡虽然我们的研究重点是使用人类细胞模型来确定 这种蛋白质复合物的溶酶体相关功能，我们预计我们的发现将具有广泛的相关性， 了解细胞如何在正常生理和疾病中对溶酶体功能障碍做出反应。特别是， C9 orf 72基因非编码区六核苷酸重复序列的扩增是最常见的家族性 额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）的病因。当前 缺乏对C9 orf 72蛋白功能的了解是了解其潜在影响的主要障碍。 在这些神经退行性疾病的发展中降低C9 orf 72蛋白水平。的成果 实验预计将产生C9 orf 72的直接目标，从而为C9 orf 72的研究提供基础。 在神经退行性疾病的背景下评估它们的失调。除了解决具体的 关于C9 orf 72蛋白功能和神经退行性疾病的问题， 使溶酶体功能与细胞需求的持续变化相匹配的机制是广泛的细胞生物学机制。 重要性与多种生理和病理背景的潜在相关性。

Project Summary/Abstract Lysosomes serve as a major site for the degradation of macromolecules and play a central role in the ability of cells to sense and respond to changes in intracellular nutrient availability. Conversely, levels of intracellular nutrients such as amino acids regulate lysosomal properties, including their biogenesis, acidification, signaling functions and subcellular position. Defining the molecular machinery that allows for this coordination of lysosome function with nutrient availability is critical for unraveling how lysosome homeostasis is maintained in health and disease. This project focuses on a heterotrimeric protein complex made up of C9orf72, SMCR8 and WDR41. Our interest in this protein complex stems from our discoveries that it is recruited to lysosomes upon amino acid deprivation and is required for both degradative functions of lysosomes as well as their ability to support activation of mTORC1 in response to acute exposure to amino acids. Our proposed research thus seeks to: 1) Elucidate the mechanisms whereby cells couple the sensing of changes in amino acid availability to the recruitment of C9orf72-SMCR8-WDR41 to lysosomes. 2) Define the direct lysosomal targets of C9orf72- SMCR8-WDR41. 3) Establish how this overall pathway is integrated into the maintenance of lysosome homeostasis. While our research focuses on using human cellular models to determine the essential lysosome-related functions of this protein complex, we anticipate that our findings will have broad relevance for understanding how cells respond to lysosome dysfunction in both normal physiology and disease. In particular, expansion of a hexanucleotide repeat in a non-coding region of the C9orf72 gene is the most common familial cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) identified to date. The current lack of understanding of C9orf72 protein function is a major obstacle to understanding the potential impact of reduced C9orf72 protein levels in the development of these neurodegenerative diseases. The results of our experiments are expected to yield direct targets of C9orf72 and will thereby provide a foundation for the evaluation of their dysregulation in the context of neurodegenerative disease. Beyond addressing specific questions about C9orf72 protein function and neurodegenerative disease, elucidation of fundamental mechanisms that match lysosome function to ongoing changes in cellular demand is of broad cell biological importance with potential relevance for multiple physiological and pathological contexts.