Diverse and dynamically regulated mRNP composition regulating translation

多样化且动态调节的 mRNP 组成调节翻译

• 批准号: 10595228
• 负责人: NICHOLAS T INGOLIA
• 金额: $ 30.04万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595228
• 关键词: Address; Automobile Driving; Cells; Choices and Control; Complement; Complex; Data; Development; Event; FRAP1 gene; Gene Expression; Genes; Growth; Human; Individual; Initiator Codon; Internet; Label; Learning; Link; MAP Kinase Gene; MAP Kinase Modules; MCT-1 gene; Mediating; Messenger RNA; PIK3CG gene; Pathway interactions; Peptide Initiation Factors; Phosphorylation; Phosphotransferases; Physiological; Physiology; Poly A; Polyadenylation; Production; Protein Biosynthesis; Protein Isoforms; Proteins; RNA; RNA-Binding Proteins; Regulation; Ribosomes; Role; Scanning; Signal Pathway; Signal Transduction; Site; Stress; Surveys; Tail; Transcript; Translation Initiation; Translational Regulation; Translations; biological adaptation to stress; in vivo; innovation; interest; link protein; mRNA Stability; mRNA Translation; messenger ribonucleoprotein; programs; protein protein interaction; recruit; response; transcriptome; translation factor

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.

摘要 细胞严格调控翻译的启动，以控制它们合成和 它们产生的每种蛋白质有多少。这种蛋白质合成的调节与翻译相匹配 水平与细胞的翻译能力和生理需求相适应。翻译启动，在 特别是，对于全球和转录特异性fic的调控来说，都是一个关键点。在规范中 翻译起始的途径，一个fi是由一个闭合环的形成而激活的 5‘-甲基鸟苷帽和3’-聚腺苷尾部之间的复杂桥联。一小块 核糖体亚基伴随着多种其他起始因子被招募到信使核糖核酸。 并进行扫描，以便在8月1日的fi开始翻译。 最近的证据表明，翻译的启动并不是这样一成不变的 路径。个别翻译因素受主要信号下游的调控 通路，包括MAP激酶级联、mTOR激酶信号和整合应激 回应。核心翻译启动因子的激活或抑制可以产生转录本- Speciific在翻译中的变化，导致了广泛的翻译重新编程。翻译： 发育调节基因还依赖于隐蔽的启动因子，如eIF2A， EIF2D和DENR/MCTS-1。 我们的动机假设是，翻译启动的这种异质格局 复合体是蛋白质合成的动态、m RNA特异性fic控制的基础。在此，我们建议 利用蛋白质和RNA的邻近标记来观察翻译的组成 在体内组装的引发复合体，并了解这种变化如何响应 生理和环境信号。我们将把这与翻译的分析结合起来。 在转录组中。综上所述，这些结果将揭示出 并展示了这些不同的途径是如何调节翻译的 表情程序。