Ubiquitin and regulation of prion induction by a short-lived protein

泛素和短寿命蛋白对朊病毒诱导的调节

基本信息

批准号：
8725684
负责人：
KEITH D WILKINSON
金额：
$ 30.36万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725684
关键词：
Actins Affect Alzheimer&apos s Disease Amino Acid Sequence Amyloid Amyloidosis Binding Biological Models Biological Process Cell physiology Cells Cellular Membrane Chemicals Complex Cytomegalovirus Infections Cytoskeleton Defect Deposition Disease Epigenetic Process Eukaryotic Cell Event Genes Goals Half-Life Homeostasis Huntington Disease Impairment In Vitro Infection Intervention Knowledge Lead Life Mammals Memory Modification Molecular Molecular Chaperones Molecular Conformation Neurodegenerative Disorders Parkinson Disease Pathway interactions Phenotype Physiological Play Polymers Post-Translational Protein Processing Prions Probability Process Protein Binding Protein Isoforms Protein Structure Initiative Proteins Quality Control Recruitment Activity Regulation Research Role Seeds Signal Transduction Site Specificity Stress Stretching Structure Synapses System Ubiquitin Ubiquitination Variant Yeasts design in vivo microbial multicatalytic endopeptidase complex overexpression oxidative damage peptide hormone polyglutamine polymerization prevent prion seeds prion-like protein folding protein misfolding relating to nervous system response sup35 termination factor trafficking trait yeast prion yeast protein

项目摘要

DESCRIPTION (provided by applicant): Prions are infectious protein isoforms that cause fatal and incurable neurodegenerative diseases in mammals and transmit heritable traits in yeast. Most prions form highly ordered fibrous polymers (amyloids), resembling the aggregates involved in other amyloidoses and neural inclusion diseases, such as Alzheimer, Parkinson, or Huntington diseases. Thus, a prion can be thought of as an amyloid that can recruit protein molecules of the same sequence, convert them into an amyloid state, and be transmitted to other cells. It is now becoming clear that in addition to their role in disease, some prions and other amyloids or amyloid-like aggregates perform important biological functions: storage of peptide hormones; attachment of microbial cells to each other or to substrates; control of epigenetic switches; adaptation to stressful environmental conditions; and long-term synaptic changes associated with memory. While many proteins form amyloids in vitro, little is known about the mechanisms of amyloid or prion formation in vivo. There are likely both basal and induced pathways that share some common features. An initial association of proteins in homomultimeric and/or heteromultimeric complexes may lead to formation of the prion "seed". The probability of such an event is increased when the amyloidogenic protein is accumulated at high concentrations in the cell and/or in a local compartment. Indeed, de novo formation of a yeast prion is promoted by overexpression of the prion protein and/or the presence of other aggregated QN-rich proteins. Processes known to affect protein levels and homeostasis, such as some physiological stresses, impairment of ubiquitin proteasome system (UPS) function, or defects in the unfolded protein response (UPR), also increase prion formation. Conversely, defects in the actin cytoskeleton diminish the rate of prion formation, suggesting that binding to cytoskeleton is important for some step(s) involved in prion nucleation. Thus, physiological stresses that cause the accumulation of prion proteins or heterologous prionogenic proteins, and that control their localization may have profound effects on the formation of prions. Lsb2 is a yeast protein whose overexpression stimulates the formation of a prion (designated [PSI+]) in the presence of overexpression of the yeast translational termination factor Sup35. Consistent with its role in prionogenesis, Lsb2 is induced by stress, ubiquitinated at K80, degraded in a proteasome-dependent fashion, and localized to actin patches. The overall goal of this research is to uncover the molecular mechanisms by which heterologous protein homeostasis participates in prion formation in eukaryotic cells. We will define the role of Lsb2 in the stress-induced formation of the [PSI+] prion. We will ask if a specific cellular localization of Lsb2 is required for prion-inducing ability, what role UPS and covalent modifications of Lsb2 play in triggering the formation of prions, and if physiological and stress- related variations in Lsb2 levels are involved in prion induction.

描述（由申请人提供）：prions是感染性蛋白质同工型，在哺乳动物中引起致命和无法治愈的神经退行性疾病，并在酵母中传播可遗传性的性状。大多数prions形成高度有序的纤维聚合物（淀粉样蛋白），类似于参与其他淀粉样蛋白和神经包容性疾病的聚集体，例如阿尔茨海默氏症，帕金森氏症或亨廷顿疾病。因此，可以将prion视为淀粉样蛋白，可以募集相同序列的蛋白质分子，将其转化为淀粉样蛋白状态，并将其传播到其他细胞。现在越来越清楚的是，除了它们在疾病中的作用外，一些王室和其他淀粉样蛋白或类似淀粉样蛋白的聚集体执行重要的生物学功能：储存肽激素；微生物细胞彼此或底物的附着；控制表观遗传开关；适应压力的环境条件；和与内存相关的长期突触变化。尽管许多蛋白质在体外形成淀粉样蛋白，但对体内淀粉样蛋白或prion形成的机制知之甚少。基础和诱导的途径可能具有共同的特征。同源物和/或异植物复合物中蛋白质的初始关联可能导致王室“种子”的形成。当淀粉样蛋白在细胞和/或局部区室中以高浓度积聚时，这种事件的可能性会增加。实际上，通过过度表达prion蛋白和/或存在其他富含QN的蛋白质，从而促进了酵母菌病毒的从头形成。已知会影响蛋白质水平和稳态的过程，例如某些生理胁迫，泛素蛋白酶体系统（UPS）功能的损害或未折叠的蛋白质反应（UPR）中的缺陷，也会增加prion形的形成。相反，肌动蛋白细胞骨架中的缺陷降低了prion形成的速率，这表明与细胞骨架的结合对于参与Prion成核的某个步骤很重要。因此，导致prion蛋白或异源pRionolic蛋白的积累的生理胁迫，控制其定位可能会对王室的形成产生深远的影响。 LSB2是一种酵母蛋白，其过表达刺激了在存在酵母翻译终止因子SUP3的情况下的prion（指定[PSI+]）的形成。 LSB2与其在prioneopinego遗率中的作用一致，由应力诱导，在K80处泛素化，以蛋白酶体依赖性的方式降解，并将其本地化为肌动蛋白斑块。这项研究的总体目标是揭示异源蛋白稳态参与真核细胞中的prion形成的分子机制。我们将定义LSB2在应力诱导的[PSI+] prion的形成中的作用。我们将询问是否需要特定的LSB2细胞定位来诱导PRION诱导能力，LSB2在触发Prions的形成中的作用以及LSB2的共价修改以及LSB2水平的生理和压力相关的变化在诱导prion prion中涉及。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.

DOI：
10.1111/mmi.12960
发表时间：
2015-05
期刊：
Molecular microbiology
影响因子：
3.6
作者：
Kiktev DA;Melomed MM;Lu CD;Newnam GP;Chernoff YO
通讯作者：
Chernoff YO

Yeast Short-Lived Actin-Associated Protein Forms a Metastable Prion in Response to Thermal Stress.

DOI：
10.1016/j.celrep.2016.12.082
发表时间：
2017-01-17
期刊：
Cell reports
影响因子：
8.8
作者：
Chernova TA;Kiktev DA;Romanyuk AV;Shanks JR;Laur O;Ali M;Ghosh A;Kim D;Yang Z;Mang M;Chernoff YO;Wilkinson KD
通讯作者：
Wilkinson KD

Physiological and environmental control of yeast prions.

DOI：
10.1111/1574-6976.12053
发表时间：
2014-03
期刊：
FEMS microbiology reviews
影响因子：
11.3
作者：
Chernova TA;Wilkinson KD;Chernoff YO
通讯作者：
Chernoff YO

Ion-specific effects on prion nucleation and strain formation.

对朊病毒成核和菌株形成的离子特异性影响。

DOI：
10.1074/jbc.m113.467829
发表时间：
2013
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Rubin,Jonathan;Khosravi,Hasan;Bruce,KathrynL;Lydon,MeganE;Behrens,SvenH;Chernoff,YuryO;Bommarius,AndreasS
通讯作者：
Bommarius,AndreasS