Diverse and dynamically regulated mRNP composition regulating translation

多样化且动态调节的 mRNP 组成调节翻译

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的细胞严格调节翻译起始，以控制它们合成的哪些蛋白质和它们产生多少蛋白质。蛋白质合成的调节与翻译相匹配与细胞的翻译能力和物理需求相关的水平。翻译启动，在特别是全球和特异性调节的关键点。在规范中翻译启动的途径，mRNA首先是通过闭环的形成而激活的在5'-甲基鸟苷帽和3'-丙二烯甲基尾尾之间进行复合桥接。一个小核糖体亚基伴随着各种其他倡议因素，被招募到mRNA 并扫描以便在8月的第一次开始翻译。最近的证据表明，翻译倡议不会继续如此统一路径。单个翻译因素受主要信号下游的调节途径，包括MAP激酶级联反应，MTOR激酶信号和集成应力回复。激活或抑制核心翻译倡议因素可能会产生转录本- 翻译的特定变化，导致广泛的翻译重编程。翻译开发的调节基因还取决于隐性起始因子，例如EIF2A， EIF2D和DENR/MCTS-1。我们激励的假设是，这种不均一的翻译启动景观复合物是蛋白质合成的动态，mRNA特异性控制的基础。在这里，我们建议使用蛋白质和RNA的接近标记，以调查翻译的组成在体内组装并了解这种响应方式的变化物理和环境信号。我们将把它与翻译分析相结合跨转录组。这些结果一起将揭示出的全部途径多样性体内翻译启动，并展示这些不同的途径如何翻译表达程序。