Systemic Regulation of ER Proteostasis

摘要 细胞应激反应途径的适当激活使细胞能够适应和维持稳态 在紧张的条件下。虽然这些途径通常被认为是在细胞内调节的，但最近的研究表明， 小鼠和C. elegans认为，某些细胞的细胞应激经历可以在远端激活应激， 其他组织的反应。例如，我们实验室的工作表明， 内质网未折叠蛋白反应（UPRER）在C.优雅， 促进抗压力和长寿。这些发现清楚地表明了系统性的重要性。 ER蛋白稳态在生物体健康中的调节。然而，这些机制和信号分子 ER蛋白质稳态的这种组织间调节的基础仍然未知。 我们的初步工作已经确定了N-乙酰葡萄糖胺（GlcNAc），蛋白质的必需代谢产物 糖基化，作为调节跨细胞ER蛋白质稳态的候选信号分子。我建议 阐明GlcNAc被应激细胞释放并被受体细胞利用的机制， 开发新的方法来检查在体内组织到组织的GlcNAc信号转导使用神经元细胞培养和C. elegans模型这项工作将揭示GlcNAc如何调节系统性ER蛋白酶抑制，并建立新的 研究糖和蛋白质糖基化如何介导细胞间通讯的技术。

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.