Novel functions of importin-alpha in RNA metabolism and the stress response

在真核细胞中，Importin-a蛋白家族(这里称为Importin-a)在细胞生理的多个方面起着重要作用。除了核运输，家庭成员还牵涉到其他重要的生物过程。最近的研究表明，Importin-a在RNA代谢和应激反应中具有新的功能。因此，我们证明了Importin-A1与Poly(A)-RNA结合。我们还发现，Importin-a家族的多个成员与细胞质应激颗粒(SGS)相关。Importin-a蛋白如何对这些关键的细胞活动做出贡献还不是很清楚。我们的研究计划将解决这些核心的生物学问题。 短期目标。我们将描述Importin-a蛋白家族的新生物学功能，因为它们与RNA代谢和应激反应有关。 长期目标。我们将(I)定义由Importin-a蛋白及其相互作用分子组成的网络，以及(Ii)确定该网络控制最终调节细胞命运的一系列不同生物过程的机制。我们的研究将为核运输因子作为调节不同细胞活动的多功能成分的作用提供新的见解。 假设。根据我们以前的研究，我们认为Importin-a调节(1)RNA代谢和(2)细胞应激反应的基本方面。 明确的目标。为了检验这些假设，我们将： (1)研究正常和应激条件下Importin-a蛋白与RNA的相互作用。 (2)明确Importin-a家族成员在有无应激条件下调控SG生物发生和影响细胞存活的机制。 基于我们最近获得的结果，我们的研究项目采取了一个新颖而令人兴奋的方向，探索了输入素-a家族意想不到的和大多未定义的特性。特别是，核运输因子和RNA新陈代谢之间的联系最近才出现，在很大程度上还不清楚。此外，Importin-a控制SGS形成的机制还有待确定。这些都是与所有真核细胞相关的重要生物学过程。因此，我们所产生的洞察力对于理解importin-a作为细胞内稳态的关键调节因子的作用至关重要。我们将通过将最先进的方法应用于RNA分析、细胞成像、定量图像分析和蛋白质分析中的先进技术，以严格的方式研究这些问题。

In eukaryotic cells, the importin-a protein family (here referred to as importin-a) contributes to multiple aspects of cell physiology. Aside from nuclear transport, family members are implicated in additional vital biological processes. Recent studies suggest that importin-a has new functions in RNA metabolism and the stress response. Thus, we demonstrated that importin-a1 binds poly(A)-RNA. We also showed that multiple members of the importin-a family associate with cytoplasmic stress granules (SGs). How importin-a proteins contribute to these crucial cellular activities is not well understood. Our research program will address these central biological questions. SHORT-TERM OBJECTIVES. We will characterize novel biological functions of the importin-a protein family as they relate to RNA metabolism and the stress response. LONG-TERM GOALS. We will (i) define the network consisting of importin-a proteins and their interactors, and (ii) determine the mechanisms through which this network controls a set of diverse biological processes that ultimately regulate cell fate. Our research will provide new insights into the roles of nuclear transport factors as multifunctional components that regulate different cellular activities. HYPOTHESES. Based on our previous studies, we propose that importin-a regulates fundamental aspects of (1) RNA metabolism, and (2) the cellular stress response. SPECIFIC AIMS. To test these hypotheses, we will: (1) Characterize the interaction of importin-a proteins with RNA under normal and stress conditions. (2) Define the mechanisms through which importin-a family members regulate SG biogenesis and impact cell survival in the presence or absence of stress. Based on results we recently obtained, our research program takes a novel and exciting direction that explores unexpected and mostly undefined properties of the importin-a family. In particular, the link between nuclear transport factors and RNA metabolism has only recently emerged and is to a large extent not understood. As well, the mechanisms through which importin-a controls the formation of SGs have yet to be determined. These are important biological processes relevant to all eukaryotic cells. Accordingly, the insights generated by us will be critical to understand the role of importin-a as key regulator of cellular homeostasis. We will examine these questions in a rigorous fashion by applying state-of-the-art methods in RNA-profiling, cell imaging, quantitative image analyses and advanced techniques in protein analysis.