Functional Studies of Ubiquilin
泛素的功能研究
基本信息
- 批准号:7372065
- 负责人:
- 金额:$ 30.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-05-01 至 2012-02-29
- 项目状态:已结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseAmyotrophic Lateral SclerosisAutophagocytosisAutophagosomeBinding ProteinsCellsClassClear CellDefectDegradation PathwayEndoplasmic ReticulumExcisionFundingGene MutationGoalsHealthHuntington DiseaseLaboratoriesLeadLocalizedLysosomesMembraneNamesNeurodegenerative DisordersNeurofibrillary TanglesNeuronsNuclear EnvelopeOrganellesOrganismParkinson DiseasePathologic ProcessesPathway interactionsProteinsResearch PersonnelRoleStressStructureSystemUbiquitinhuman diseasemembermulticatalytic endopeptidase complexnovelprotein degradationprotein misfoldingubiquilin
项目摘要
DESCRIPTION (provided by investigator): A common theme that is emerging from studies of neurodegenerative disorders is the realization that many of them are associated, or caused, by defects in protein degradation pathways involving either the ubiquitin-proteasome system or autophagy. The ubiquitin-proteasome degradation pathway is the major pathway used in cells in which misfolded, damaged, and unwanted proteins are first tagged with a chain of four or more ubiquitin molecules and is then recognized and degraded by the proteasome. The autophagy pathway is similar in many respects to the ubiquitin-proteasome degradation pathway, except that proteins as well as organelles are targeted to the lysosome instead of the proteasome. At present it is not known how cells select one or both of these pathways to degrade a particular protein. Our laboratory identified ubiquilin, the founding member of a new class of proteins that appears to regulate protein degradation in cells. During the last funding period, we discovered that ubiquilin interacts with a novel endoplasmic reticulum (ER)- and nuclear envelope-localized protein that we named erasin. We found that erasin promotes endoplasmic reticulum- associated protein degradation (ERAD), a regulated pathway in which misfolded proteins in the ER are extracted and degraded in a ubiquitin-dependent manner by the proteasome. We found that erasin levels are increased by ER stress and that both ubiquilin and erasin protein levels are increased in neurons undergoing neurofibrillary degeneration in Alzheimer's disease. In other studies we found that ubiquilin and erasin interact functionally in ERAD and that they colocalize and are required for autophagosome formation during autophagy. The goal of this proposal is to characterize the functional role of ubiquilin and erasin proteins in cells, with particular emphasis of their roles in ERAD and autophagy. We propose three aims. In Aim 1, we will determine the role of ubiquilin-erasin interaction in ERAD. In Aim 2, we will determine the role of ubiquilin-erasin interaction in autophagy. Finally in Aim 3 we will characterize erasin-interacting proteins and determine the structure and mechanism of targeting of the ER-membrane-localization sequence of erasin. Together these studies should lead to a better understanding of the function of ubiquilin and erasin in protein degradation pathways and the role of the proteins in health and pathological processes.
Proteins carry out many vital functions in organisms, but to do so, they need to be correctly folded. Unfortunately proteins tend to misfold, either because they contain genetic mutations or because of environmental influences. In fact, accumulation of misfolded proteins is now known to cause many human diseases, particularly neurodegenerative diseases like Alzheimer's disease, Huntingtons's disease, Lou Gehrig's disease, and Parkinson's disease. This proposal is directed towards studies of ubiquilin and erasin, two new proteins that we discovered that are involved in the removal of misfolded proteins in cells. The results obtained from this proposal will not only lead to a better understanding of how misfolded proteins are cleared from cells, but also could lead to new therapies to treat human diseases caused by protein misfolding.
描述(由研究者提供):从神经退行性疾病研究中出现的一个共同主题是认识到其中许多与蛋白质降解途径缺陷有关或由其引起,涉及泛素-蛋白酶体系统或自噬。泛素-蛋白酶体降解途径是细胞中使用的主要途径,其中错误折叠、受损和不需要的蛋白质首先用四个或更多个泛素分子的链标记,然后被蛋白酶体识别和降解。自噬途径在许多方面类似于泛素-蛋白酶体降解途径,除了蛋白质以及细胞器靶向溶酶体而不是蛋白酶体。目前尚不清楚细胞如何选择这两种途径中的一种或两种来降解特定的蛋白质。我们的实验室发现了泛素,这是一类新蛋白质的创始成员,似乎可以调节细胞中的蛋白质降解。在上一个资助期间,我们发现ubiquilin与一种新的内质网(ER)和核膜定位蛋白相互作用,我们将其命名为erasin。我们发现erasin促进内质网相关蛋白降解(ERAD),这是一种调节途径,其中ER中的错误折叠蛋白被蛋白酶体以泛素依赖性方式提取和降解。我们发现ER应激会增加erasin水平,并且阿尔茨海默病中经历神经原纤维变性的神经元中的遍在蛋白和erasin蛋白水平都增加。在其他研究中,我们发现泛素和erasin在ERAD中功能性相互作用,并且它们共定位并且是自噬过程中自噬体形成所需的。本提案的目标是表征泛素和erasin蛋白在细胞中的功能作用,特别强调它们在ERAD和自噬中的作用。我们提出三个目标。在目的1中,我们将确定泛素-erasin相互作用在ERAD中的作用。在目标2中,我们将确定泛素-erasin相互作用在自噬中的作用。最后,在目标3中,我们将表征erasin相互作用蛋白,并确定erasin的ER膜定位序列的结构和靶向机制。总之,这些研究将有助于更好地了解泛素和erasin在蛋白质降解途径中的功能以及这些蛋白质在健康和病理过程中的作用。
蛋白质在生物体中执行许多重要功能,但要做到这一点,它们需要正确折叠。不幸的是,蛋白质往往会错误折叠,要么是因为它们含有基因突变,要么是因为环境影响。事实上,现在已知错误折叠蛋白质的积累会导致许多人类疾病,特别是神经退行性疾病,如阿尔茨海默病、亨廷顿病、卢伽雷病和帕金森病。这项建议是针对研究ubiquilin和erasin,这两个新的蛋白质,我们发现,参与在细胞中错误折叠的蛋白质的去除。从这一提议中获得的结果不仅可以更好地了解错误折叠的蛋白质是如何从细胞中清除的,而且还可以导致治疗蛋白质错误折叠引起的人类疾病的新疗法。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Mervyn J Monteiro其他文献
Mervyn J Monteiro的其他文献
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{{ truncateString('Mervyn J Monteiro', 18)}}的其他基金
Deciphering the role of ER stress in ALS pathogenesis caused by UBQLN2 mutations
解读 ER 应激在 UBQLN2 突变引起的 ALS 发病机制中的作用
- 批准号:
10207794 - 财政年份:2017
- 资助金额:
$ 30.75万 - 项目类别:
Deciphering the role of ER stress in ALS pathogenesis caused by UBQLN2 mutations
解读 ER 应激在 UBQLN2 突变引起的 ALS 发病机制中的作用
- 批准号:
9318653 - 财政年份:2017
- 资助金额:
$ 30.75万 - 项目类别:
Mechanistic studies and therapeutics for ALS-FTD linked to UBQLN2 mutations
与 UBQLN2 突变相关的 ALS-FTD 的机制研究和治疗
- 批准号:
10063576 - 财政年份:2017
- 资助金额:
$ 30.75万 - 项目类别:
Quality control of APP cleavage by RING-finger ubiquitin ligases
通过环指泛素连接酶进行 APP 切割的质量控制
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9308437 - 财政年份:2017
- 资助金额:
$ 30.75万 - 项目类别:
Mechanistic studies and therapeutics for ALS/FTD linked to UBQLN2 mutations
与 UBQLN2 突变相关的 ALS/FTD 的机制研究和治疗
- 批准号:
10373433 - 财政年份:2017
- 资助金额:
$ 30.75万 - 项目类别:
Generation of a mouse model to monitor ERAD in neurons
生成监测神经元 ERAD 的小鼠模型
- 批准号:
9331759 - 财政年份:2016
- 资助金额:
$ 30.75万 - 项目类别:
Generation of a mouse model to monitor ERAD in neurons
生成监测神经元 ERAD 的小鼠模型
- 批准号:
9251591 - 财政年份:2016
- 资助金额:
$ 30.75万 - 项目类别:
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