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

在压力时期，细胞会重新安排基因表达程序和代谢途径的优先顺序，以限制损害并在压力消除之前存活下来。这些细胞应激反应复杂且知之甚少，但越来越多的证据表明，它们在限制感染的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。自噬就是这种细胞应激反应的一个例子，字面意思是“自我吞噬”。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循环，允许细胞在饥饿的压力下存活，从而为生存提供必要的细胞构建块和能量。有趣的是，压力还被证明通过影响全球信使RNA(MRNA)的周转和翻译来影响基因的表达。应激反应的一个核心特征是对翻译的快速和可逆的抑制，这可以防止异常蛋白的积累，并促进关键应激反应蛋白的产生。翻译上不活跃的信使核蛋白复合体形成大的细胞质聚集体，称为应激颗粒(SGS)。在应激过程中，SGS在控制翻译机制方面发挥着核心作用，它是翻译不活跃的转录本被分拣并被送到重新启动或降解的位置(如加工小体)的位置。尽管它们在控制基因表达和维持细胞内稳态方面发挥着重要的、可能是互补的作用，但迄今为止，自噬和SGS/p-Body之间的关系还没有被探索过。目前的提议旨在利用一套分子工具和高分辨率成像技术来阐明这些复杂的体内平衡机制之间的关系。这项工作将为在压力时期控制基因表达的基本细胞过程提供新的见解。

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.