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Investigating the adaptive role of heat-induced biomolecular condensates in translational regulation

研究热诱导生物分子缩合物在翻译调节中的适应性作用

基本信息

批准号：
10686023
负责人：
Caitlin Wong
金额：
$ 4.77万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686023
关键词：
5&apos Untranslated Regions Affect Behavior Binding Bioinformatics Body Temperature Cell Communication Cell Survival Cells Cellular Stress Chicago Computational Biology Environment Exposure to Fever Flow Cytometry Fluorescence Anisotropy Growth Heat Stress Disorders Heat-Shock Response High temperature of physical object Immune Impairment In Vitro Luciferases Measures Mediating Methods Modeling Molecular Chaperones Molecular Probes Nature Orthologous Gene Pathogenicity Pathway interactions Physical condensation Physiological Play Poly(A)-Binding Protein I Production Proteins RNA-Binding Proteins Recovery Repression Research Research Personnel Resources Role Saccharomyces cerevisiae Saccharomycetales Shapes Signal Transduction Stress System Temperature Testing Transcript Translating Translation Initiation Translational Regulation Translational Repression Translations Universities Work Yeasts attenuation biological adaptation to stress career cell growth design environmental change fitness in vivo misfolded protein protein aggregation protein folding protein function protein misfolding response skills stoichiometry thermophilic organism translation assay

项目摘要

Project Summary/Abstract When cells encounter heat, they undergo a number of archetypal intracellular changes: global attenuation of translation, synthesis of molecular chaperones, and the formation of intracellular protein aggregates. These aggregates were long thought to be the result of misfolded proteins, however, recent work has suggested that these assemblies may be the adaptive result of biomolecular condensation. It has remained unclear how biomolecular condensation functions to help cells survive heat stress. Here, I propose to investigate a connection between heat-induced condensation and translation of molecular chaperones. Previous work has demonstrated that poly(A)-binding protein (Pab1) condenses during heat shock in yeast and disrupting Pab1 condensation impairs cellular growth during stress, indicating that stress-triggered condensation of Pab1 is a part of the adaptive stress response. This finding motivated me to investigate why Pab1 is important for cell growth during stress. Pab1 acts as a translational repressor by binding transcripts with A-rich 5’ Untranslated Regions (5’UTRs), including its own transcript. Interestingly, the transcripts of molecular chaperones produced during stress have A-rich 5’UTRs, and these molecular chaperones go on to re-solubilize Pab1. My preliminary work shows that soluble Pab1 can repress translation of endogenous transcripts with A-rich 5’UTRs, while Pab1 condensation inhibits this effect. This suggests an autoregulatory mechanism through which heat-triggered condensation of Pab1 facilitates high level translation of stress- induced chaperones, whose capacity to re-solubilize Pab1 leads to repressed translation after sufficient chaperones have been produced. To test this model, I will probe the molecular basis of Pab1 translational repression using in vitro translation assays and fluorescence anisotropy. I will also carry out a bioinformatic analysis of A-rich 5’UTRs to identify sequence features that are conserved and test whether they contribute to Pab1 repression. Next, I will design yeast strains to perturb Pab1 condensation in vivo to test how this change affects the production of molecular chaperones. Finally, Pab1 condensation does not completely explain how heat shock transcripts are specifically translated in the midst of global translational attenuation, so I will investigate how A-rich 5’UTRs can promote selective translation, using similar in vitro and in vivo methods. My proposed model connects direct environmental sensing by condensation to the adaptive cellular stress response and helps shape our understanding of how cells respond to heat in other contexts, such as immune cells in fever. This research will be done at the University of Chicago with Dr. D. Allan Drummond and will build my skillset in in vitro, in vivo, and computational biology, preparing me for a career as an independent investigator.

项目总结/文摘