Defining the function and mechanism of regulatory ribosomal ubiquitylation

定义调节性核糖体泛素化的功能和机制

基本信息

  • 批准号:
    10319621
  • 负责人:
  • 金额:
    $ 35.17万
  • 依托单位:
  • 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:
    2021-01-01 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Protein homeostasis (proteostasis) relies on the continual surveillance and removal of defective translation products resulting from the relatively high error rates associated with mRNA translation. Proteostasis dysfunction has been implicated in human aging-related pathologies, including many neurodegenerative disorders, suggesting that molecular strategies to either limit the production of erroneous translation products or elevate protein quality control capacity may provide therapeutic benefit. As such, characterizing cellular mechanisms that regulate translation activity or ribosome-associated quality control function is needed to enable molecular control over proteostasis under normal and stress conditions. We have discovered conserved, site-specific, regulatory ribosomal ubiquitylation (RRub) events on individual 40S ribosomal proteins that represent a new axis of translational control. Our objective is to determine the molecular mechanisms by which RRub impacts ribosome-associated quality control and the integrated stress response pathway. Toward this goal, we have identified the critical ubiquitin ligases and deubiquitylating enzymes that mediate these RRub events. We have generated a unique and powerful set of genome-edited cell lines that will enable molecular dissection of RRub and the cellular pathways which require RRub for proper function. Our hypothesis is that manipulation of RRub machinery can be utilized to alter translation both during and following acute proteotoxic stress. Furthermore, we hypothesize that cells with elevated translation activity and/or elevated levels of damaged or cleaved mRNAs will require enhanced quality control activity for function and survival. To probe these hypotheses, we will: (1) dissect ubiquitin-dependent and independent mechanisms within the ribosome-associated quality control pathway; (2) determine physiologically-relevant cellular conditions that require elevated RQC activity; and (3) characterize how RRub reshapes translation at steady-state and during activation and recovery of the integrated stress response. Research outcomes achieved by the proposed studies will mechanistically determine how terminally stalled ribosomes are sensed and resolved via the RQC pathway. We will also define how RRub alters stress response pathways through regulation of ribosome abundance or translation activity. Several ribosomal proteins and translation-associated factors are regulatory ubiquitylation targets which suggests that our research strategy can be broadly applied to other targets to enable protein biogenesis control at multiple steps. Successful completion of the proposed research will provide substantial progress toward our long-term goal of combating aging-associated human pathology through the development of molecular strategies to modify cellular responses to chronic proteotoxic stress and improve cellular fitness following proteostasis insults.
项目摘要 蛋白质稳态依赖于持续的监视和去除有缺陷的翻译 与mRNA翻译相关的相对高的错误率导致的产物。蛋白质稳态 功能障碍与人类衰老相关的病理学有关,包括许多神经退行性疾病, 疾病,这表明,分子策略,要么限制生产错误的翻译产品, 或提高蛋白质质量控制能力可提供治疗益处。因此,表征细胞 需要调节翻译活性或核糖体相关质量控制功能的机制, 在正常和应激条件下能够对蛋白质稳态进行分子控制。我们已经发现 个体40 S核糖体上保守的、位点特异性的、调节性核糖体泛素化(RRub)事件 这些蛋白质代表了一种新的翻译控制轴。我们的目标是确定 RRub影响核糖体相关质量控制和综合应激反应的机制 通路为了实现这一目标,我们已经确定了关键的泛素连接酶和去泛素化酶, 介导这些RRub事件。我们已经产生了一组独特而强大的基因组编辑细胞系, 将使RRub的分子解剖和需要RRub正常功能的细胞通路成为可能。 我们的假设是,操纵RRub机制可以用来改变翻译过程中, 急性蛋白毒性应激后此外,我们假设翻译活性升高的细胞 和/或升高水平的受损或切割的mRNA将需要增强的质量控制活性, 和生存为了探讨这些假设,我们将:(1)解剖泛素依赖性和非依赖性 核糖体相关质量控制途径内的机制;(2)确定生理相关的 需要升高的RQC活性的细胞条件;和(3)表征RRub如何在 稳态以及在整合应激反应的激活和恢复期间。研究成果 所提出的研究将从机制上确定如何感知末端停滞的核糖体 并通过RQC途径解决。我们还将定义RRub如何通过以下途径改变应激反应途径: 核糖体丰度或翻译活性的调节。几种核糖体蛋白和与之相关的 因子是调控泛素化的靶点,这表明我们的研究策略可以广泛应用于 以使蛋白质生物合成控制在多个步骤。圆满完成拟议的 研究将为我们对抗与衰老相关的人类疾病的长期目标提供实质性进展。 通过发展分子策略来改变细胞对慢性蛋白毒性的反应, 应激和改善蛋白质稳态损伤后的细胞适应性。

项目成果

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Eric J Bennett其他文献

Hematopoietic Stem Cells Depend upon Aggrephagy to Maintain Protein Homeostasis and Self-Renewal Activity
  • DOI:
    10.1182/blood-2022-163857
  • 发表时间:
    2022-11-15
  • 期刊:
  • 影响因子:
  • 作者:
    Bernadette Anne Chua;Connor J Lennan;Mary Jean Sunshine;Ashu Chawla;Lorena H San Jose;Daniela Dreifke;Eric J Bennett;Robert Signer
  • 通讯作者:
    Robert Signer
How degrading! Trapped translation factors get trashed.
多么有辱人格啊!
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Pierce W Ford;Eric J Bennett
  • 通讯作者:
    Eric J Bennett
Simply quantifying ubiquitin complexity
仅仅量化泛素的复杂性
  • DOI:
    10.1038/nmeth.1651
  • 发表时间:
    2011-07-28
  • 期刊:
  • 影响因子:
    32.100
  • 作者:
    Eric J Bennett;J Wade Harper
  • 通讯作者:
    J Wade Harper

Eric J Bennett的其他文献

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{{ truncateString('Eric J Bennett', 18)}}的其他基金

Leveraging ubiquitin-dependent regulatory mechanisms to improve proteome quality in health and disease
利用泛素依赖性调节机制提高健康和疾病中的蛋白质组质量
  • 批准号:
    10552479
  • 财政年份:
    2023
  • 资助金额:
    $ 35.17万
  • 项目类别:
Defining the function and mechanism of regulatory ribosomal ubiquitylation
定义调节性核糖体泛素化的功能和机制
  • 批准号:
    10543532
  • 财政年份:
    2021
  • 资助金额:
    $ 35.17万
  • 项目类别:
Leveraging orphan protein degradation pathways to target cells with unstable proteomes
利用孤儿蛋白降解途径靶向具有不稳定蛋白质组的细胞
  • 批准号:
    10004157
  • 财政年份:
    2018
  • 资助金额:
    $ 35.17万
  • 项目类别:
Leveraging orphan protein degradation pathways to target cells with unstable proteomes
利用孤儿蛋白降解途径靶向具有不稳定蛋白质组的细胞
  • 批准号:
    10251955
  • 财政年份:
    2018
  • 资助金额:
    $ 35.17万
  • 项目类别:

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