Elucidating the Relations of Heat Shock Factors, Molecular Chaperones and Prions

阐明热休克因子、分子伴侣和朊病毒的关系

• 批准号: 8213745
• 负责人: LIMING LI
• 金额: $ 32.12万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213745
• 关键词: Anabolism; Animal Model; Anxiety; Bovine Spongiform Encephalopathy; Cells; Chronic Wasting Disease; Complex; Creutzfeldt-Jakob Syndrome; Data Analyses; Epidemic; Etiology; Evaluation; Future; Gene Targeting; Goals; Health; Heat shock proteins; Heat-Shock Response; Limes; Link; Maintenance; Methods; Molecular; Molecular Chaperones; Molecular Conformation; Neurodegenerative Disorders; Outcome; Play; Principal Investigator; Prion Diseases; Prions; Production; Protein Structure Initiative; Proteins; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Stress; Suggestion; Testing; Variant; base; cell type; conformational conversion; drug discovery; interest; novel; novel therapeutics; programs; protein folding; research study; response; success; yeast prion

DESCRIPTION (provided by applicant): Despite decades of scientific research and heightening public and governmental anxiety over the potential dangers of infectious proteins and their role in epidemics such as new variant Creutzfeldt-Jacob disease, Mad Cow disease, and chronic Wasting disease, the mechanisms responsible for the conversion of a normal cellular protein into an infectious prion protein continue to defy understanding. The cellular factors instrumental to the protein conformational changes that result in prion formation, as well as those factors necessary for the subsequent stabilization of the altered prion conformation, remain a mystery. Considering that prion formation and inheritance are tightly related to the protein folding machinery, we propose to investigate the link between prion formation and heat shock transcriptional factors (HSFs). HSFs are evolutionally conserved transcriptional factors responsible for the biosynthesis of the majority of molecular chaperones, which are essential for protecting cells from extreme harsh conditions by refolding or dis-aggregating denatured proteins produced during the stress. Several molecular chaperones are also shown to play essential roles in prion propagation. Using the budding yeast Saccharomyces cerevisiae as the model organism, we propose to elucidate the relationship between HSFs and prion formation/propagation. Our long-term goal of the proposed research is to identify protein factors whose functions are regulated by HSFs and are essential for prion formation/propagation. The specific aims are: 1) to examine the regulatory role of heat shock protein 90kDa (Hsp90) complex in de novo formation and "strain" maintenance of [PSI+]; 2) to test if HSF and Hsp90 complex regulate other yeast prions. We will investigate if the effects of HSF and Hsp90/cochaperones are [PSI+] specific: 3) to identify additional novel factors that are HSF targets and responsible for prion formation and propagation. PUBLIC HEALTH RELEVANCE: Prion diseases are a group of infectious neurodegenerative diseases also known as transmissible spongiform encephalopathies. The molecular mechanisms govern the etiology of prion diseases are poorly understood. We propose to identify cellular factors that are required for prion conformational conversion and are important for subsequent stabilization of the acquired prion conformation. The success of proposed study will likely provide target genes for future drug discovery and new therapeutics for the devastating prion diseases.

描述（由申请人提供）：尽管经过数十年的科学研究以及对传染性蛋白质的潜在危险及其在流行病中的作用，例如新变体Creutzfeldt-Jacob疾病，疯狂的牛病以及慢性浪费疾病，但导致正常细胞蛋白质对感染性蛋白质的对转换的机制，使人们对感染蛋白质的转化，使人对感染蛋白质的差异，并增加了公众和政府的焦虑。对蛋白质构象变化的启发性的细胞因子，导致prion形成prion的形成，以及随后稳定的prion病毒构象所必需的因素仍然是一个谜。考虑到王室形成和遗传与蛋白质折叠机械密切相关，我们建议研究prion形成与热休克转录因子（HSF）之间的联系。 HSF是导致大多数分子伴侣生物合成的进化保守的转录因子，这对于通过重新折叠或脱离压力过程中产生的变性蛋白来保护细胞免受极端恶劣条件至关重要。还显示几个分子伴侣在prion传播中起着重要作用。我们将酿酒酵母的萌芽酵母菌作为模型生物，我们建议阐明HSFS与Prion形成/传播之间的关系。我们提出的研究的长期目标是鉴定其功能受HSF调节的蛋白质因子，对于prion形成/传播至关重要。具体目的是：1）检查热休克蛋白90KDA（HSP90）复合物在从头形成和[PSI+]的“应变”维持中的调节作用； 2）测试HSF和HSP90复合物是否调节其他酵母菌。我们将调查HSF和HSP90/联合酮的影响[PSI+]特定：3）确定其他新型因素是HSF靶标，并负责prion的形成和传播。公共卫生相关性：病毒疾病是一组感染性神经退行性疾病，也称为可传染性海绵状脑病。分子机制控制着私人疾病的病因，知之甚少。我们建议鉴定prion构构转化所需的细胞因子，对于随后稳定获得的prion构构象很重要。拟议研究的成功可能会为未来的药物发现和毁灭性的毒品疾病提供目标基因。

项目成果

Cytoplasmic expression of mouse prion protein causes severe toxicity in Caenorhabditis elegans.

• DOI: 10.1016/j.bbrc.2008.05.132
• 发表时间: 2008-08
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Kyung-Won Park;Liming Li

Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy.

• DOI: 10.1007/s13238-011-1014-5
• 发表时间: 2011-02
• 期刊: Protein & cell
• 影响因子: 21.1
• 作者: Fushimi K;Long C;Jayaram N;Chen X;Li L;Wu JY
• 通讯作者: Wu JY

Newly identified prions in budding yeast, and their possible functions.

• DOI: 10.1016/j.semcdb.2011.03.003
• 发表时间: 2011-07
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Crow ET;Li L
• 通讯作者: Li L

The Yeast Prion [SWI(+)] Abolishes Multicellular Growth by Triggering Conformational Changes of Multiple Regulators Required for Flocculin Gene Expression.

• DOI: 10.1016/j.celrep.2015.11.060
• 发表时间: 2015-12-29
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Du Z;Zhang Y;Li L
• 通讯作者: Li L

Spreading of a prion domain from cell-to-cell by vesicular transport in Caenorhabditis elegans.

秀丽隐杆线虫中朊病毒结构域通过囊泡运输从细胞传播到细胞。

• DOI: 10.1371/journal.pgen.1003351
• 发表时间: 2013
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Nussbaum-Krammer,CarmenI;Park,Kyung-Won;Li,Liming;Melki,Ronald;Morimoto,RichardI
• 通讯作者: Morimoto,RichardI