mRNA Template-free Protein Elongation: a New Paradigm for Quality Control at the Ribosome

mRNA 无模板蛋白质延伸：核糖体质量控制的新范式

基本信息

批准号：
10673842
负责人：
Onn Brandman
金额：
$ 32.33万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10673842
关键词：
Address Alanine Amino Acids Behavior Biochemical Biochemistry Biological Biological Assay C-terminal Cell Line Cells Code Curiosities Data Disease Drosophila genus Eukaryotic Cell Failure Foundations Functional disorder Future Genetic Genomic approach Goals Human Image Impairment In Vitro Investigation Knowledge Life Link Lysine Mediating Messenger RNA Modeling Nerve Degeneration Parkinson Disease Pathologic Pathology Process Production Protein Biosynthesis Proteins Quality Control Reporter Research Research Project Summaries Ribosomal Proteins Ribosomes Role System Tail Testing Threonine Toxic effect Transfer RNA Translating Translations Ubiquitin Work Yeasts cell type coping human disease in vivo multicatalytic endopeptidase complex mutant neuromuscular novel strategies programs protein degradation response ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary This research effort seeks to increase fundamental knowledge about how cells handle failures in protein synthesis and how these failures can lead to disease. Protein synthesis by the ribosome can abnormally halt (“stall”) for numerous reasons, including faulty mRNA, insufficient availability of translation components, and genetic errors. Handling these failures is critical, as abnormal responses to stalled protein synthesis have been demonstrated to cause neurodegeneration. To cope with this burden, eukaryotic cells employ a process called Ribosome-associated Quality Control (RQC) that detects stalled ribosomes and promotes degradation of the protein that the ribosome was previously synthesizing (the “stalled nascent chain”). As part of RQC, we discovered that the protein Rqc2 hijacks the ribosome to append Carboxy-terminal Alanine and Threonine residues (“CAT tails”) to the stalled nascent chain. CAT tails benefit cells by marking stalled nascent chains for degradation. Curiously, CAT tails can also harm cells by forming toxic aggregates that impair cellular viability. How CAT tails possess these seemingly contradictory behaviors (beneficial vs. toxic) remains unclear. This research program will address this knowledge gap by using biochemical, cell biological, and genomic approaches to study: 1) how cells synthesize CAT tails , 2) how cells degrade CAT tails, and 3) how CAT tails behave in metazoans. This study will elucidate a fundamental mechanism cells use to protect themselves from failed protein synthesis and uncover the causes and consequences of its misregulation.

项目概要这项研究工作旨在增加有关细胞如何处理蛋白质故障的基础知识合成以及这些失败如何导致核糖体的蛋白质合成异常停止。（“停滞”）有多种原因，包括 mRNA 错误、翻译组件可用性不足以及处理这些失败至关重要，因为对停滞的蛋白质合成的异常反应已经发生。为了应对这种明显的负担，真核细胞采用了一种称为神经退行性变的过程。核糖体相关质量控制 (RQC)，可检测停滞的核糖体并促进核糖体的降解核糖体先前合成的蛋白质（“停滞的新生链”）作为 RQC 的一部分，我们。发现蛋白质 Rqc2 劫持核糖体以附加羧基末端丙氨酸和苏氨酸停滞的新生链上的残基（“CAT 尾巴”）通过标记停滞的新生链来使细胞受益。奇怪的是，CAT 尾部也会通过形成损害细胞活力的有毒聚集体来伤害细胞。 CAT 尾巴如何具有这些看似矛盾的行为（有益与有毒）仍不清楚。研究计划将通过利用生物化学、细胞生物学和基因组学来解决这一知识差距研究方法：1) 细胞如何合成 CAT 尾，2) 细胞如何降解 CAT 尾，3) CAT 尾如何这项研究将阐明细胞用来保护自身免受侵害的基本机制。蛋白质合成失败并揭示其错误调节的原因和后果。