Stress Granules in Yeast and Mammals

项目摘要 该基金的目标是了解压力的组装、动力学和功能 控制基因表达的颗粒。应激颗粒是不翻译的细胞质颗粒， 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，并被认为在以下方面发挥作用： 调节其常驻mRNA的翻译或降解，特别是在应激期间。第二、 在神经元中形成与应激颗粒相关的组装体，并在调节突触可塑性中发挥作用 （McCann等人，2011; Barbee等人，2006年）。因此，了解压力颗粒将有助于理解 其他类似的mRNP组件。最后，异常应力颗粒的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）、 骨骼和一些肌肉肌病这些疾病可以由RNA结合突变引起 蛋白质，如hnRNPA 1或TDP-43，其增加应激颗粒组装和淀粉样蛋白形成， 或通过AAA-ATPase VCP中的突变，其减少应激颗粒清除。而且这些 疾病的特征在于存在含有标记物的细胞质RNA-蛋白质聚集体 压力颗粒。鉴于这种重要性在正常的压力反应和病理条件下， 理解正常和异常应激颗粒的形成和功能是至关重要的。在这份补助金中， 我们建立在我们最近对应激颗粒蛋白质组和转录组的分析基础上， 应激颗粒形成对mRNA功能的影响，靶向应激颗粒的mRNA的机制， 以及mRNA-mRNA反式相互作用在应激组装和维持中的新作用 颗粒。本提案所涉及的具体问题是： I）应激颗粒组装对mRNA稳定性和衰变的影响是什么？ II）mRNA分配到应激颗粒的机制是什么？ 3. RNA-RNA相互作用在应激颗粒组装中的作用是什么？ 这些目标的完成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颗粒如何形成和影响受影响的基因表达。 组织中

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.