Mechanisms of cytosolic proteostasis in yeast

酵母细胞质蛋白稳态机制

基本信息

项目摘要

Nearly 50 major diseases ranging from diabetes to neurodegenerative disorders including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) diseases have been linked to protein misfolding and aggregation. Cells grow and proliferate under the constant threat of damage from endogenous reactive oxygen species (ROS), exogenous oxidants and reactive electrophiles. Cytosolic protein cysteines are almost exclusively maintained in the reduced state, and cysteine oxidation caused by oxidative stress is predicted to result in significant misfolding and aggregation. However, relatively little is known about the consequences of redox imbalance on protein homeostasis (proteostasis). Furthermore, the roles of cellular reduction-oxidation (redox) buffering pathways, including the thioredoxin and glutathione systems, in maintaining cytosolic proteostasis are not well understood. We seek to understand the interplay between cytoprotective stress response pathways and the machinery employed to maintain proteostasis. Published and preliminary results detailed in the proposal lead us to hypothesize that induction of the cytoprotective heat shock response (HSR) by redox imbalance is mediated in part by a cysteine switch in the principal protein chaperone Hsp70 (Ssa1 in budding yeast) and that thiol redox buffering plays a significant role in maintenance of cytosolic proteostasis. The primary objectives of this renewal application are to determine the impacts of thiol-reactive stress on cytoplasmic protein biogenesis and protein quality control and to elucidate the regulatory interactions between oxidant and unfolded protein responses, through three distinct lines of investigation. In Specific Aim 1 we will define the mechanism by which the key molecular chaperone Ssa1/Hsp70 regulates the HSR through modulation of transcriptional activity by the master heat shock transcription factor Hsf1. Specific Aim 2 will investigate the consequences of thiol- reactive stress on Ssa1/Hsp70 activity and cellular functions, including how the Ssa1/Hsp70 redox switch regulates the HSR, and determine the roles of the highly conserved redox buffering systems in mediating thiol-reactive stress. In Specific Aim 3, we will determine the impacts of protein thiol modification on general cytosolic proteostasis using proteomic and genetic approaches. The work outlined in this proposal will reveal the mechanistic connections between cellular redox and protein quality control networks by exploiting the tractable yeast model system. These results in turn will guide future development of therapeutic interventions targeting ROS- and protein quality control-based disorders.
近50种主要疾病,从糖尿病到神经退行性疾病 包括阿尔茨海默氏病(AD)、帕金森氏病(PD)和亨廷顿氏病(HD)的疾病已经被 与蛋白质错误折叠和聚集有关。细胞生长和增殖下, 内源性活性氧(ROS)、外源性 氧化剂和反应性亲电体。胞质蛋白半胱氨酸几乎完全是 维持在还原状态,由氧化应激引起的半胱氨酸氧化, 预测会导致显著的错误折叠和聚集。然而,相对来说, 了解氧化还原失衡对蛋白质稳态的影响 (蛋白质稳态)。此外,细胞还原-氧化(氧化还原)缓冲的作用 途径,包括硫氧还蛋白和谷胱甘肽系统,在维持细胞质 蛋白质稳态还没有被很好地理解。我们试图理解 细胞保护性应激反应途径和用于维持 蛋白质稳态已公布的初步结果和提案中详细说明的结果使我们 推测氧化还原诱导细胞保护性热休克反应(HSR 不平衡部分由主要蛋白伴侣中的半胱氨酸开关介导 Hsp 70(芽殖酵母中的Ssa 1),巯基氧化还原缓冲在 维持胞质蛋白质稳定。本续期申请的主要目的 确定巯基反应胁迫对细胞质蛋白质生物合成的影响 和蛋白质质量控制,并阐明氧化剂之间的调节相互作用 和未折叠的蛋白质反应,通过三个不同的调查路线。在特定 目的1:明确关键分子伴侣Ssa 1/Hsp 70在细胞内表达的机制 通过调节转录活性调节HSR由主热 休克转录因子Hsf 1。具体目标2将研究巯基的后果- 反应性应激对Ssa 1/Hsp 70活性和细胞功能的影响,包括 Ssa 1/Hsp 70氧化还原开关调节HSR,并决定了Hsp 70在HSR中的作用。 保守的氧化还原缓冲系统介导硫醇反应性应激。在具体目标3中, 我们将确定蛋白质巯基修饰对一般细胞溶质的影响, 使用蛋白质组学和遗传学方法进行蛋白质稳定。本提案中概述的工作 将揭示细胞氧化还原和蛋白质质量控制之间的机械联系 利用易处理的酵母模型系统的网络。这些结果反过来将指导 以ROS和蛋白质质量为目标的治疗干预的未来发展 控制型障碍

项目成果

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KEVIN ANTHONY MORANO其他文献

KEVIN ANTHONY MORANO的其他文献

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{{ truncateString('KEVIN ANTHONY MORANO', 18)}}的其他基金

Chaperone-mediated mechanisms of cellular proteostasis
分子伴侣介导的细胞蛋白质稳态机制
  • 批准号:
    10620389
  • 财政年份:
    2023
  • 资助金额:
    $ 2.46万
  • 项目类别:
Mechanisms of cytosolic proteostasis in yeast
酵母细胞质蛋白稳态机制
  • 批准号:
    9896845
  • 财政年份:
    2018
  • 资助金额:
    $ 2.46万
  • 项目类别:
2017 Stress Proteins in Growth, Development and Disease GRC/GRS: Maintaining proteostasis over a lifetime.
2017 生长、发育和疾病中的应激蛋白 GRC/GRS:一生中维持蛋白质稳态。
  • 批准号:
    9389763
  • 财政年份:
    2017
  • 资助金额:
    $ 2.46万
  • 项目类别:
Hsp110 protein chaperone function in yeast
Hsp110 蛋白伴侣在酵母中的功能
  • 批准号:
    7856487
  • 财政年份:
    2009
  • 资助金额:
    $ 2.46万
  • 项目类别:
Hsp110 protein chaperone function in yeast
Hsp110 蛋白伴侣在酵母中的功能
  • 批准号:
    7388182
  • 财政年份:
    2006
  • 资助金额:
    $ 2.46万
  • 项目类别:
Hsp110 protein chaperone function in yeast
Hsp110 蛋白伴侣在酵母中的功能
  • 批准号:
    8234723
  • 财政年份:
    2006
  • 资助金额:
    $ 2.46万
  • 项目类别:
Hsp110 protein chaperone function in yeast
Hsp110 蛋白伴侣在酵母中的功能
  • 批准号:
    7210539
  • 财政年份:
    2006
  • 资助金额:
    $ 2.46万
  • 项目类别:
Hsp110 protein chaperone function in yeast
Hsp110 蛋白伴侣在酵母中的功能
  • 批准号:
    7090987
  • 财政年份:
    2006
  • 资助金额:
    $ 2.46万
  • 项目类别:
Hsp110 protein chaperone function in yeast
Hsp110 蛋白伴侣在酵母中的功能
  • 批准号:
    7591629
  • 财政年份:
    2006
  • 资助金额:
    $ 2.46万
  • 项目类别:
Hsp110 protein chaperone function in yeast
Hsp110 蛋白伴侣在酵母中的功能
  • 批准号:
    8788364
  • 财政年份:
    2006
  • 资助金额:
    $ 2.46万
  • 项目类别:

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