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.
真核生物中所有新合成的蛋白质的大约三分之一进入内质 网状(ER)。一旦与此隔室相关,这些新生的多肽是 经过翻译处理,获得了本机确认,低聚并进行分类 细胞外分泌或传递到其他细胞器。但是,许多引起疾病的原因 突变会损害蛋白质折叠和成熟,这又会产生聚集 - 俯卧的物种。避开涉及蛋白质积累的灾难性作用 聚集体,错误折叠的蛋白底物为:(i)由分子伴侣相关的分子伴侣选择 用ER,(ii)用泛素修饰,(iii)通过称为细胞质 逆转录分配,(IV)被26S蛋白酶体降解。布罗德斯基和同事命名 这种相关的降解(Erad)以及过去21年中的这种途径 在布罗德斯基实验室中定义了这种事件序列的分子机制。到 日期,约有80种人类疾病与ERAD途径有关,> 1200次出版物已有 在此途径的各个方面撰写。持续的努力正在定义 几种与ERAD相关疾病的病理生理基础。同时, 布罗德斯基实验室(Brodsky Lab)揭示了关键组件如何在Erad期间进行每个步骤进行编排。在 过去5年,该实验室发表了64篇论文,并开发了工具和技术 提供对导致泛素化选择机制的前所未有的观点 逆转录和不同底物的降解。然而,最近发现 要求提出更多挑战研究指示:必要的这些下一个努力 将需要其他方法开发和追求长期目标。具体的 研究计划将解决的问题包括:哪些生化特征定义了 ERAD底物?哪些因素足以驱动ERAD底物的逆转录, 其中一些易于聚集?与ER相关的蛋白酶在与 26S蛋白酶体破坏稳定整合到ER膜中的底物,并 那可能是抗转化的耐药性吗?而且,如何转递转转位的膜蛋白 - 从ER解放出来后,哪个可以驻留在细胞质中? 这些问题的答案,这些问题是该领域研究的核心,将大大显着 促进对面对蛋白质应激的细胞健康如何维持的理解 以及如何出现ERAD相关疾病并可能纠正。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A positive genetic selection for transmembrane domain mutations in HRD1 underscores the importance of Hrd1 complex integrity during ERAD.
  • DOI:
    10.1007/s00294-022-01227-1
  • 发表时间:
    2022-04
  • 期刊:
  • 影响因子:
    2.5
  • 作者:
  • 通讯作者:
Hsp40s play distinct roles during the initial stages of apolipoprotein B biogenesis.
  • DOI:
    10.1091/mbc.e21-09-0436
  • 发表时间:
    2022-02-01
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Kumari D;Fisher EA;Brodsky JL
  • 通讯作者:
    Brodsky JL
The generation of detergent-insoluble clipped fragments from an ERAD substrate in mammalian cells.
  • DOI:
    10.1038/s41598-023-48769-z
  • 发表时间:
    2023-12-06
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
  • 通讯作者:
A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes.
  • DOI:
    10.1016/j.nbd.2023.106196
  • 发表时间:
    2023-08
  • 期刊:
  • 影响因子:
    6.1
  • 作者:
    Bhatia TN;Jamenis AS;Abbas M;Clark RN;Miner KM;Chandwani MN;Kim RE;Hilinski W;O'Donnell LA;Luk KC;Shi Y;Hu X;Chen J;Brodsky JL;Leak RK
  • 通讯作者:
    Leak RK
Fundamental and translational research in Cystic Fibrosis - why we still need it.
囊性纤维化的基础和转化研究 - 为什么我们仍然需要它。
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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:
    $ 1.76万
  • 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:
    $ 1.76万
  • 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:
    $ 1.76万
  • 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:
    10626023
  • 财政年份:
    2019
  • 资助金额:
    $ 1.76万
  • 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:
    $ 1.76万
  • 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:
    $ 1.76万
  • 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:
    $ 1.76万
  • 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:
    $ 1.76万
  • 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:
    $ 1.76万
  • 项目类别:
Model Organisms
模式生物
  • 批准号:
    8734390
  • 财政年份:
    2008
  • 资助金额:
    $ 1.76万
  • 项目类别:

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ER and post-ER quality control of integral membrane proteins
完整膜蛋白的 ER 和 ER 后质量控制
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