Signal-Induced Regulation of Alternative RNA Processing

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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.