ER and post-ER quality control of integral membrane proteins

完整膜蛋白的 ER 和 ER 后质量控制

基本信息

项目摘要

Approximately one-third of all newly synthesized proteins in eukaryotes enter the endoplasmic reticulum (ER). Once associated with this compartment, these nascent polypeptides are post- translationally processed, acquire their native confirmations, oligomerize, and are sorted for extracellular secretion or delivery to other organelles. However, many disease-causing mutations compromise protein folding and maturation, which in turn can generate aggregation- prone species. To off-set the catastrophic effects that accompany the accumulation of protein aggregates, misfolded protein substrates are: (i) selected by molecular chaperones associated with the ER, (ii) modified with ubiquitin, (iii) delivered to the cytoplasm via a process known as retrotranslocation, and (iv) degraded by the 26S proteasome. Brodsky and colleagues named this pathway ER associated degradation (ERAD), and over the past 21 years many of the molecular mechanisms underlying this sequence of events were defined in the Brodsky lab. To date, ~80 human diseases are linked to the ERAD pathway and >1,200 publications have been authored on various aspects of this pathway. Ongoing efforts are defining the pathophysiological foundation of several ERAD-related disorders. In parallel, members of the Brodsky lab have revealed how key components orchestrate each step during ERAD. In the past 5 years, the lab has published 64 papers, and tools and technologies were developed that provide an unprecedented view of the mechanisms that lead to the selection, ubiquitination, retrotranslocation, and degradation of diverse substrates. Nevertheless, recent discoveries dictate that more challenging research directions are pursued: By necessity, these next efforts will require additional method development and a pursuit of longer-term goals. Specific questions that the research program will address include: What biochemical features define an ERAD substrate? Which factors are sufficient to drive the retrotranslocation of ERAD substrates, some of which are aggregation-prone? Do ER-associated proteases function in tandem with the 26S proteasome to destroy substrates that are stably integrated into the ER membrane, and thus might be retrotranslocation resistant? And, how are retrotranslocated membrane proteins— which can reside in the cytosol after being liberated from the ER—retained in a soluble state? Answers to these questions, which lie at the core of research in the field, will significantly advance an understanding of how cellular health is maintained in the face of proteotoxic stress as well as how ERAD-associated diseases arise and might be rectified.
在真核生物中,大约三分之一的新合成蛋白质进入内质网, 网织膜(ER)。一旦与该隔室结合,这些新生多肽就被后- 经过初步处理,获得它们的天然确认,寡聚化,并被分类, 细胞外分泌或递送到其他细胞器。然而,许多疾病 突变损害蛋白质折叠和成熟,这反过来又会产生聚集- 倾向性物种。以抵消蛋白质积累带来的灾难性影响 聚集体,错误折叠的蛋白质底物:(i)通过与蛋白质聚集体结合的分子伴侣选择, (ii)用泛素修饰,(iii)通过称为 逆易位,和(iv)由26 S蛋白酶体降解。Brodsky和他的同事命名为 这种途径ER相关的降解(ERAD),在过去的21年中,许多 这一系列事件背后的分子机制是在Brodsky实验室中定义的。到 迄今为止,约80种人类疾病与ERAD途径有关, 在这条道路的各个方面撰写。正在进行的努力正在确定 几种ERAD相关疾病的病理生理学基础。与此同时, Brodsky实验室揭示了ERAD过程中关键组件如何协调每个步骤。在 在过去的5年里,该实验室发表了64篇论文,开发了工具和技术, 提供了一个前所未有的机制,导致选择,泛素化, 逆易位和不同底物的降解。然而,最近的发现 要求追求更具挑战性的研究方向:必要时,这些下一步的努力 将需要额外的方法开发和追求长期目标。具体 该研究计划将解决的问题包括:什么生化特征定义了一个 ERAD底物?哪些因素足以驱动ERAD底物的反向易位, 其中一些是聚合倾向?ER相关蛋白酶是否与 26 S蛋白酶体破坏稳定整合到ER膜中的底物,和 因此可能具有逆转录抗性?以及,如何逆转录转移膜蛋白- 在从ER释放后可以驻留在胞质溶胶中-保持在可溶状态? 这些问题是该领域研究的核心, 推进对细胞健康如何在面对蛋白毒性应激时得以维持的理解 以及ERAD相关疾病的发生和纠正。

项目成果

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JEFFREY L. BRODSKY其他文献

JEFFREY L. BRODSKY的其他文献

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{{ truncateString('JEFFREY L. BRODSKY', 18)}}的其他基金

The role of FIT2 in VLDL assembly, hepatic triglyceride homeostasis, and lipoprotein atherogenicity
FIT2 在 VLDL 组装、肝甘油三酯稳态和脂蛋白致动脉粥样硬化中的作用
  • 批准号:
    10638637
  • 财政年份:
    2023
  • 资助金额:
    $ 36.84万
  • 项目类别:
Interinstitutional Program in Cell and Molecular Biology: A Graduate Training Path to Promote Traditional and Non-Traditional Professional Outcomes
细胞和分子生物学机构间项目:促进传统和非传统专业成果的研究生培训路径
  • 批准号:
    10421289
  • 财政年份:
    2020
  • 资助金额:
    $ 36.84万
  • 项目类别:
Interinstitutional Program in Cell and Molecular Biology: A Graduate Training Path to Promote Traditional and Non-Traditional Professional Outcomes
细胞和分子生物学机构间项目:促进传统和非传统专业成果的研究生培训路径
  • 批准号:
    10192522
  • 财政年份:
    2020
  • 资助金额:
    $ 36.84万
  • 项目类别:
ER and Post-ER Quality Control of Integral Membrane Proteins
完整膜蛋白的 ER 和 ER 后质量控制
  • 批准号:
    10798491
  • 财政年份:
    2019
  • 资助金额:
    $ 36.84万
  • 项目类别:
ER and post-ER quality control of integral membrane proteins
完整膜蛋白的 ER 和 ER 后质量控制
  • 批准号:
    10176534
  • 财政年份:
    2019
  • 资助金额:
    $ 36.84万
  • 项目类别:
ER and post-ER quality control of integral membrane proteins
完整膜蛋白的 ER 和 ER 后质量控制
  • 批准号:
    10428489
  • 财政年份:
    2019
  • 资助金额:
    $ 36.84万
  • 项目类别:
Modulating Hsp70-dependent proteostasis in Alzheimer's Disease
调节阿尔茨海默病中 Hsp70 依赖性蛋白质稳态
  • 批准号:
    10118403
  • 财政年份:
    2019
  • 资助金额:
    $ 36.84万
  • 项目类别:
FASEB SRC on Protein Folding in the Cell
FASEB SRC 关于细胞中蛋白质折叠的研究
  • 批准号:
    8720195
  • 财政年份:
    2014
  • 资助金额:
    $ 36.84万
  • 项目类别:
2009 Stress Proteins in Growth, Development, and Disease Gordon Research Conferen
2009 年生长、发育和疾病中的应激蛋白戈登研究会议
  • 批准号:
    7663377
  • 财政年份:
    2009
  • 资助金额:
    $ 36.84万
  • 项目类别:
Model Organisms
模式生物
  • 批准号:
    8734390
  • 财政年份:
    2008
  • 资助金额:
    $ 36.84万
  • 项目类别:

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