Signal-Induced Regulation of Alternative RNA Processing

项目摘要 该项目的最终目标是了解细胞信号传导和RNA加工在塑造中的相互作用。 细胞基因表达和功能。本供资期的具体重点是解开 存在于信号通路和RNA加工事件之间的调节连接，以及RNA 结合蛋白（RBPs），维持这些连接。几十年的研究表明，细胞信号 信号通路是控制细胞功能以响应环境线索的核心。同样，所有 RNA加工的步骤，包括选择性剪接、选择性多聚腺苷酸化和调节mRNA 稳定性，可以被调节以决定最终mRNA和蛋白质的身份或丰度。历史上， 关于细胞信号传导对基因表达的影响的大多数工作集中在转录的调节上。 因此，细胞信号传导如何影响RNA加工的各种机制，以及相反，如何影响RNA加工的各种机制。 RNA加工塑造了细胞对环境挑战的反应，仍然是大部分未开发的领域。 这些研究对我们广泛理解细胞活动至关重要。T细胞活化提供了一个很好的治疗方法。 复杂细胞反应的模型系统，因为多个信号传导通路在细胞的下游被触发。 抗原接合，并单独和协同作用以诱导T细胞效应子功能。已经充分 证明了T细胞活化导致可变剪接、聚腺苷酸化和mRNA稳定性的变化。 此外，这些RNA加工事件的变化影响了另外的信号传导途径，例如细胞凋亡 和炎症，它们是对T细胞活化的关键次级反应。然而，许多问题 关于RNA加工和信号传导之间的调节联系，包括确定 将信号传导与RNA加工联系起来的RBP，了解加工事件的功能影响 由其他途径上的一个信号触发，并确定单个RBP如何协调多个步骤， RNA加工该提案将通过以下方式解决信号诱导的RNA加工的这些未回答的问题： 利用最近的结果和系统来确定选择性剪接如何控制细胞凋亡和干扰素 活化T细胞中的应答信号，控制交替多聚腺苷酸化和mRNA 稳定性的反应T细胞信号，和一个潜在的新机制，为调节翻译的 RBP CELF 2.总之，这些研究将提供关于信号和RNA相互作用的新见解。 在T细胞活化过程中塑造细胞功能。由于这里研究的信号通路是 与细胞生长和死亡有关，这些研究中获得的见解将广泛适用于T细胞以外的其他细胞。 生物学此外，这些研究将揭示新的模式，关于分子机制， RBP协调控制RNA加工中的多个步骤。因此，这些实验的结果将 显著增加对控制蛋白质组表达的机制的一般理解， 细胞对环境信号的反应。

Project Summary The ultimate goal of this project is to understand the interplay of cell signaling and RNA processing in shaping cellular gene expression and function. The specific focus of the current funding period is in unraveling the regulatory connections that exist between signaling pathways and RNA processing events, and the RNA binding proteins (RBPs) that maintain these connections. Decades of work have revealed that cell signaling pathways are central to controlling cellular function in response to environmental cues. Similarly, all of the steps of RNA processing, including alternative splicing, alternative polyadenylation and regulated mRNA stability, can be regulated to dictate the identity or abundance of the final mRNA and proteins. Historically, most work on the impact of cell signaling on gene expression has focused on the regulation of transcription. Therefore, how cell signaling impinges on the various mechanisms of RNA processing, and conversely, how RNA processing shapes the cellular response to environmental challenges, remain largely unexplored areas of research that are critical to our broad understanding of cellular activity. T cell activation provides an excellent a model system for complex cellular responses, as multiple signaling pathways are triggered downstream of antigen engagement and act, individually and cooperatively, to induce T cell effector functions. It has been well documented that T cell activation leads to changes in alternative splicing, polyadenylation and mRNA stability. Moreover, changes in these RNA processing events impact additional signaling pathway such as apoptosis and inflammation, which are critical secondary responses to T cell activation. However, many questions regarding the regulatory connections between RNA processing and signaling remain, including identifying the RBPs that link signaling to RNA processing, understanding the functional impact of processing events triggered by one signal on other pathways, and determining how individual RBPs coordinate multiple steps of RNA processing. This proposal will address these unanswered questions of signal-induced RNA processing by leveraging recent results and systems to determine how alternative splicing controls apoptosis and interferon responsive signaling in activated T cells, the proteins that control alternative polyadenylation and mRNA stability in response to T cell signaling, and a potential new mechanism for the regulation of translation by the RBP CELF2. Together these studies will provide novel insight regarding the interplay of signaling and RNA processing in shaping cellular function during T cell activation. Since the signaling pathways studied here are related to cell growth and death, the insight gained in these studies will be broadly applicable far beyond T cell biology. In addition, these studies will reveal new paradigms regarding the molecular mechanisms by which RBPs coordinately control multiple steps in RNA processing. Thus, results from these experiments will significantly increase the general understanding of the mechanisms that control proteome expression and cellular function in response to environmental cues.