Stress Granules in Yeast and Mammals

项目概要 这笔赠款的目标是了解压力的组装、动态和功能 颗粒控制基因表达。应激颗粒是非翻译的细胞质颗粒 当翻译起始受到限制时形成的 mRNA 和蛋白质。应力颗粒对于 三个原因。首先，它们隔离 mRNA 和 mRNA 结合蛋白，并被认为在 调节其驻留 mRNA 的翻译或降解，特别是在应激期间。第二， 与应激颗粒相关的组件在神经元中形成并在调节突触可塑性中发挥作用 （McCann 等人，2011 年；Barbee 等人，2006 年）。因此，了解应力颗粒将有助于理解 其他类似的 mRNA 组件。最后，异常的应力颗粒积累似乎是一个原因 多系统病理学中的事件，称为包涵体肌病 (IBM)，包括 肌萎缩侧索硬化症 (ALS)、额颞叶变性 (FTLD)、佩吉特氏病 骨骼和一些肌肉肌病。这些疾病可能是由 RNA 结合突变引起的 蛋白质，例如 hnRNPA1 或 TDP-43，可增加应激颗粒组装和淀粉样蛋白形成， 或通过 AAA-ATPase VCP 突变，降低应激颗粒清除率。而且，这些 疾病的特征是存在含有标记物的细胞质 RNA 蛋白聚集体 应力颗粒。鉴于在正常应激反应和病理条件下的重要性， 了解正常和异常的应激颗粒的形成和功能至关重要。在这笔赠款中， 我们基于最近对应激颗粒蛋白质组和转录组的分析来确定效果 应激颗粒形成对 mRNA 功能的影响，将 mRNA 靶向应激颗粒的机制， 以及反式 mRNA-mRNA 相互作用对应激组装和维持的新作用 颗粒。该提案解决的具体问题是： I) 应激颗粒组装对 mRNA 稳定性和衰变有何影响？ II) mRNA 划分成应激颗粒的机制是什么？ III) RNA-RNA 相互作用在应激颗粒组装中的作用是什么？ 完成这些目标将揭示应力颗粒组装和功能的基本原理， 包括深入了解病理性 RNP 颗粒如何形成以及如何影响受影响的基因表达 组织。

PROJECT SUMMARY The goals of this grant are to understand the assembly, dynamics, and functions of stress granules in the control of gene expression. Stress granules are cytoplasmic granules of untranslating mRNAs and proteins that form when translation initiation is limiting. Stress granules are important for three reasons. First, they sequester mRNAs and mRNA binding proteins and are thought to play a role in regulating the translation or degradation of its resident mRNAs, particularly during stress. Second, assemblies related to stress granules form in neurons and play a role in modulating synaptic plasticity (McCann et al., 2011; Barbee et al., 2006). Thus, understanding stress granules will help to understand other similar mRNP assemblies. Finally, aberrant stress granule accumulation appears to be a causative event in a multisystem pathology, referred to as inclusion body myopathy (IBM) that includes Amyotrophic Lateral Sclerosis (ALS), Frontotemporal lobar degeneration (FTLD), Paget's disease of bone and some muscle myopathies. These diseases can be caused by mutations in RNA binding proteins, such as hnRNPA1 or TDP-43, which increase stress granule assembly and amyloid formation, or by mutations in the AAA-ATPase VCP, which decrease stress granule clearance. Moreover, these diseases are characterized by the presence of cytoplasmic RNA-protein aggregates that contain markers of stress granules. Given this importance in both normal stress responses and in pathological conditions, an understanding of normal and aberrant stress granule formation and function is critical. In this grant, we build on our recent analyses of the stress granule proteome and transcriptome to determine the effect of stress granule formation on mRNA function, the mechanisms that target mRNAs to stress granules, and the novel role of mRNA-mRNA interactions in trans on the assembly and maintenance of stress granules. The specific questions addressed in this proposal are: I) What is the impact of stress granule assembly on mRNA stability and decay? II) What are the mechanisms of mRNA partitioning into stress granules? III) What is the role of RNA-RNA interactions in stress granule assembly? Completion of these aims will reveal fundamental principles of stress granule assembly and function, including insights into how pathological RNP granules form and impact gene expression in affected tissues.