"Understanding the role of autophagy in the control of RNA trafficking, triage and translation"

“了解自噬在控制 RNA 运输、分类和翻译中的作用”

• 批准号: 341940-2012
• 负责人: McCormick, Craig
• 金额: $ 1.89万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=527537
• 关键词: Understanding; role; autophagy; control; RNA

In times of stress, cells re-prioritize their gene expression programs and metabolic pathways in order to limit damage and survive until the stress is resolved. These cellular stress responses are complex and poorly understood, but accumulating evidence indicates that they play important roles in limiting the damage of infection, and monitoring aberrant cellular behaviour that might lead to cancer. One example of such a cellular stress response is autophagy, which literally means 'self-eating'. Autophagy is an evolutionarily conserved process that permits cells to survive the stress of starvation by promoting the degradation and recycling of a variety of cellular structures, thereby providing essential cellular building blocks and energy for survival. Interestingly, stress has also been shown to impact gene expression by influencing global messenger RNA (mRNA) turnover and translation. A central feature of the stress response is rapid and reversible inhibition of translation, which prevents the accumulation of aberrant proteins and facilitates the production of key stress response proteins. Translationally inactive mRNA-protein complexes nucleate the formation of large cytoplasmic aggregates known as stress granules (SGs). SGs play a central role in controlling the translation machinery during stress, serving as sites where translationally-inactive transcripts are triaged and routed to sites of re-initiation or degradation (e.g. processing-bodies). Despite their important and perhaps complementary roles in controlling gene expression and maintaining cellular homeostasis, the relationship between autophagy and SGs/p-bodies has not been explored to date. The current proposal is aimed at elucidating the relationship between these complex homeostatic mechanisms, using a suite of molecular tools and high-resolution imaging techniques. This work will provide new insights into the fundamental cellular processes that control gene expression during times of stress.

在压力下，细胞会重新调整其基因表达程序和代谢途径的优先级，以限制损伤并存活到压力得到解决。这些细胞应激反应是复杂的，人们对其了解甚少，但越来越多的证据表明，它们在限制感染损害和监测可能导致癌症的异常细胞行为方面发挥着重要作用。这种细胞应激反应的一个例子是自噬，字面意思是“自我进食”。自噬是一种进化上保守的过程，通过促进各种细胞结构的降解和再循环，从而提供生存所必需的细胞构建模块和能量，使细胞能够在饥饿的压力下存活。有趣的是，压力也被证明通过影响整体信使RNA（mRNA）的周转和翻译来影响基因表达。应激反应的一个中心特征是对翻译的快速和可逆的抑制，其防止异常蛋白质的积累并促进关键应激反应蛋白质的产生。翻译失活的mRNA-蛋白质复合物使称为应激颗粒（SG）的大细胞质聚集体的形成成核。SG在应激期间控制翻译机制中起着核心作用，充当将无活性转录物分类并路由到重新起始或降解位点（例如加工体）的位点。尽管它们在控制基因表达和维持细胞内稳态方面具有重要且可能是互补的作用，但迄今为止尚未探索自噬与SGs/p体之间的关系。目前的提案旨在使用一套分子工具和高分辨率成像技术阐明这些复杂的自我平衡机制之间的关系。这项工作将为在压力下控制基因表达的基本细胞过程提供新的见解。