Systemic Regulation of ER Proteostasis

内质网蛋白质稳态的系统调节

• 批准号: 10396458
• 负责人: Chung Yin Kimberly Tsui
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396458
• 关键词: Aging; Biological Assay; CRISPR screen; Caenorhabditis elegans; Cell Communication; Cell Culture Techniques; Cell Line; Cells; Cellular Stress; Cellular Stress Response; Chemistry; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Detection; Disease; Distal; Endoplasmic Reticulum; Enzymes; GRP78 gene; Genes; Glycoproteins; Health; Homeostasis; Human; Induced pluripotent stem cell derived neurons; Intestines; Knock-out; Label; Longevity; Mediating; Methods; Microscopy; Modeling; Mus; Neurons; Organism; Pathway interactions; Pharmacology; Phosphines; Physiological; Protein Glycosylation; Proteins; Proteome; Quality Control; Regulation; Reperfusion Injury; Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Supplementation; Techniques; Testing; Tissues; Toxic effect; Tunicamycin; Up-Regulation; Work; biological adaptation to stress; endoplasmic reticulum stress; experience; experimental study; extracellular; genome-wide; glycosylation; hepatoma cell; improved; in vivo; induced pluripotent stem cell; insight; liquid chromatography mass spectrometry; nerve stem cell; novel; novel strategies; promoter; protein folding; protein metabolite; protein misfolding; proteostasis; proteotoxicity; response; stressor; sugar; unpublished works

Abstract Proper activation of cellular stress response pathways allows cells to adapt and maintain homeostasis during stressful conditions. While these pathways are typically thought to be regulated within a cell, recent studies in mice and C. elegans suggest that cellular stress experience in certain cells can distally activate stress response in other tissues. For example, work from our lab have shown that neuronal activation of the endoplasmic reticulum Unfolded Protein Response (UPRER) induces UPRER in the intestine of C. elegans, promoting stress resistance and longevity. These findings clearly demonstrates the importance of systemic regulation of ER proteostasis in organismal health. However, the mechanisms and the signaling molecules underlying such inter-tissue regulation of ER proteostasis remain unknown. Our preliminary work has identified N-acetylglucosamine (GlcNAc), an essential metabolite for protein glycosylation, as a candidate signaling molecule for regulating ER proteostasis across cells. I propose to elucidate mechanisms by which GlcNAc is released by stressed cells and utilized by recipient cells, and to develop novel methods to examine in vivo tissue-to-tissue GlcNAc signaling using neuronal cell culture and C. elegans models. This work will uncover how GlcNAc regulates systemic ER proteostasis, and establish novel techniques to study how sugars and protein glycosylation mediate cell-cell communication.

摘要 细胞应激反应通路的适当激活使细胞能够适应和维持动态平衡 在紧张的条件下。虽然这些通路通常被认为是在细胞内调节的，但最近 对小鼠和线虫的研究表明，在某些细胞中经历的细胞应激可以远端激活应激 在其他组织中的反应。例如，我们实验室的研究表明，神经元的激活 内质网未折叠蛋白应答(UPRER)诱导线虫肠道UPRER， 增强抗压能力，延年益寿。这些发现清楚地表明了系统性的重要性 内质网蛋白平衡在生物体健康中的调控。然而，其机制和信号分子 在这种组织间调节ER蛋白平衡的基础上仍不清楚。 我们的初步工作确定了N-乙酰氨基葡萄糖(GlcNAc)，这是蛋白质的一种重要代谢物 糖基化，作为调节细胞内ER蛋白平衡的候选信号分子。我提议 阐明GlcNAc被应激细胞释放并被受体细胞利用的机制，以及 发展新的方法，利用神经细胞培养和C. 优雅的模特。这项工作将揭示GlcNAc如何调节系统的内质网蛋白平衡，并建立新的 研究糖和蛋白质糖基化如何调节细胞间通讯的技术。