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）对细胞生理学的多个方面做出贡献。除了核运输外，家族成员还参与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结合poly（A）-RNA。我们还发现，多个成员的importin-a家族与细胞质应激颗粒（SGs）。importin-a蛋白如何参与这些重要的细胞活动还不清楚。我们的研究计划将解决这些核心生物学问题。短期替代品。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蛋白及其相互作用物组成的网络，（ii）确定该网络控制一系列最终调节细胞命运的不同生物过程的机制。我们的研究将为核转运因子作为调节不同细胞活动的多功能组分的作用提供新的见解。假设。 基于我们以前的研究，我们提出importin-a调节（1）RNA代谢和（2）细胞应激反应的基本方面。具体目标。为了检验这些假设，我们将：*（1）表征在正常和应激条件下importin-a蛋白与RNA的相互作用。* （2）定义importin-a家族成员在存在或不存在应激的情况下调节SG生物发生并影响细胞存活的机制。* 基于我们最近获得的结果，我们的研究计划采取了一个新颖而令人兴奋的方向，探索了importin-a家族的意想不到和大多数未定义的特性。特别是，核转运因子和RNA代谢之间的联系只是最近才出现，在很大程度上是不理解的。同样，importin-a控制SGs形成的机制尚未确定。这些是与所有真核细胞相关的重要生物过程。因此，我们所产生的见解将是至关重要的，以了解重要的作用-a作为细胞内稳态的关键调节器。我们将通过应用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.**