Diverse and dynamically regulated mRNP composition regulating translation
Diverse and dynamically regulated mRNP composition regulating translation
批准号:
10595228
负责人:
NICHOLAS T INGOLIA
金额:
$30.04万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-04-01 至 2027-01-31
关键词:
AddressAutomobile DrivingCellsChoices and ControlComplementComplexDataDevelopmentEventFRAP1 geneGene ExpressionGenesGrowthHumanIndividualInitiator CodonInternetLabelLearningLinkMAP Kinase GeneMAP Kinase ModulesMCT-1 geneMediatingMessenger RNAPIK3CG genePathway interactionsPeptide Initiation FactorsPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPoly APolyadenylationProductionProtein BiosynthesisProtein IsoformsProteinsRNARNA-Binding ProteinsRegulationRibosomesRoleScanningSignal PathwaySignal TransductionSiteStressSurveysTailTranscriptTranslation InitiationTranslational RegulationTranslationsbiological adaptation to stressin vivoinnovationinterestlink proteinmRNA StabilitymRNA Translationmessenger ribonucleoproteinprogramsprotein protein interactionrecruitresponsetranscriptometranslation factor
中文摘要
摘要
英文摘要
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.
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