Stress Granules in Yeast and Mammals

项目总结 这项资助的目标是了解压力的组装、动态和功能。 颗粒在基因表达调控中的作用。应激颗粒是未翻译的细胞质颗粒 翻译启动受限时形成的mRNAs和蛋白质。应激颗粒是重要的 有三个原因。首先，它们隔离mRNAs和mRNAs结合蛋白，并被认为在 调节其驻留的mRNAs的翻译或降解，特别是在应激期间。第二, 与应激颗粒相关的集合体在神经元中形成，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，了解压力颗粒将有助于理解 其他类似的mRNP组件。最后，异常的应激颗粒堆积似乎是一种原因。 多系统病理中的事件，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)，Paget病 骨骼和一些肌肉疾病。这些疾病可由rna结合突变引起。 蛋白质，如hnRNPA1或TDP-43，可增加应激颗粒组装和淀粉样蛋白的形成， 或者是由于AAA-ATPase VCP的突变，降低了应激颗粒的清除。此外，这些 疾病的特征是存在含有标记物的细胞质RNA-蛋白质聚集体。 压力颗粒。鉴于在正常应激反应和病理条件下的这种重要性， 了解正常和异常应力颗粒的形成和功能是至关重要的。在这笔赠款中， 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的基础上来确定其影响 应激颗粒的形成对mRNA功能的影响，靶向mRNAs应激颗粒的机制， 反式反应中的信使核糖核酸-信使核糖核酸相互作用在应激的组装和维持中的新作用 颗粒。这项提案涉及的具体问题如下： I)应激颗粒组装对信使核糖核酸的稳定性和衰变有何影响？ Ii)应激颗粒的mRNA分割机制是什么？ Iii)RNA-RNA相互作用在应激颗粒组装中的作用是什么？ 这些目标的完成将揭示应力颗粒组装和作用的基本原理， 包括对病理性RNP颗粒如何形成和影响受影响的基因表达的见解 纸巾。

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.