Diverse and dynamically regulated mRNP composition regulating translation

摘要 细胞严格调节翻译起始，以控制它们合成哪些蛋白质， 每种蛋白质的产量这种蛋白质合成的调节与翻译相匹配 与细胞的翻译能力和生理需求相匹配。翻译启动，在 特别是，这是全球和转录特异性监管的关键点。在正典中 作为翻译起始的途径，mRNA首先通过形成闭环而被激活， 5 '-甲基鸟苷帽和3'-聚腺苷酸尾之间的复合物桥接。一个小 核糖体亚基，伴随着各种其他起始因子，被募集到mRNA中 并扫描以便在第一个八月开始翻译。 最近的证据表明，翻译启动并没有进行这样的统一 通路单个翻译因子受到主要信号下游的调节 通路，包括MAP激酶级联，mTOR激酶信号传导，以及整合应激 反应核心翻译起始因子的激活或抑制可以产生转录本- 翻译中的特定变化，导致广泛的翻译重编程。翻译 发育调节基因也依赖于隐蔽起始因子如eIF 2A， eIF 2D和DENR/MCTS-1。 我们的动机假设是，这种异质景观的翻译启动 复合物是蛋白质合成的动态、mRNA特异性控制的基础。在此，我们建议 利用蛋白质和RNA的邻近标记，以调查翻译的组成 在体内组装的起始复合物，并了解这种变化是如何响应 生理和环境信号。我们将结合翻译的分析， 在转录组中。总之，这些结果将揭示各种途径， 在体内的翻译起始，并显示这些不同的途径如何介导翻译 表达程序。

ABSTRACT Cells tightly regulate translation initiation in order to control which proteins they synthesize and how much of each protein they produce. This regulation of protein synthesis matches translation levels with the cell's translational capacity and physiological needs. Translation initiation, in particular, is a key point for both global and transcript-specific regulation. In the canonical pathway for translation initiation, an mRNA is first activated by the formation of a closed-loop complex bridging between the 5'-methylguanosine cap and the 3'-polyadenylate tail. A small ribosomal subunit, accompanied by a variety of other initiation factors, is recruited to the mRNA and scans in order to begin translation at the first AUG. Recent evidence suggests that translation initiation does not proceed down such a uniform pathway. Individual translation factors are subject to regulation downstream of major signaling pathways, including MAP kinase cascades, mTOR kinase signaling, and the integrated stress response. Activation or inhibition of core translation initiation factors can produce transcript- specific changes in translation, leading to broad translational reprogramming. Translation of developmentally regulated genes also depends on cryptic initiation factors such as eIF2A, eIF2D, and DENR/MCTS-1. Our motivating hypothesis is that this heterogeneous landscape of translation initiation complexes underlies dynamic, mRNA-specific control of protein synthesis. Here, we propose to use proximity labeling of protein and RNA in order to survey the composition of translation initiation complexes that assemble in vivo and understanding how this changes in response to physiological and environmental signals. We will couple this with an analysis of translational across the transcriptome. Together, these results will reveal the full diversity of pathways for translation initiation in vivo and show how these different pathways mediate translational expression programs.