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

描述（由申请人提供）：尽管经过数十年的科学研究，公众和政府对感染性蛋白质的潜在危险及其在流行病（如新变异型克雅氏病、疯牛病和慢性消耗病）中的作用日益焦虑，但负责将正常细胞蛋白质转化为感染性朊病毒蛋白质的机制仍不清楚。导致朊病毒形成的蛋白质构象变化的细胞因子，以及随后改变的朊病毒构象的稳定所必需的那些因子，仍然是一个谜。考虑到朊病毒的形成和遗传与蛋白质折叠机制密切相关，我们建议研究朊病毒的形成和热休克转录因子（HSFs）之间的联系。HSF是进化上保守的转录因子，负责大多数分子伴侣的生物合成，其对于通过重折叠或解聚在应激期间产生的变性蛋白质来保护细胞免受极端恶劣条件的影响是必需的。几种分子伴侣也被证明在朊病毒传播中发挥重要作用。使用芽殖酵母酿酒酵母作为模式生物，我们建议阐明HSFs和朊病毒的形成/繁殖之间的关系。我们提出的研究的长期目标是确定蛋白质因子，其功能由HSFs调节，并对朊病毒的形成/繁殖至关重要。具体目标是：1）检测热休克蛋白90 kDa（Hsp 90）复合物在[PSI+]从头形成和“株”维持中的调节作用; 2）检测HSF和Hsp 90复合物是否调节其他酵母朊病毒。我们将研究HSF和Hsp 90/辅伴侣蛋白的作用是否是[PSI+]特异性的：3）鉴定作为HSF靶点并负责朊病毒形成和繁殖的其他新因子。公共卫生相关性：朊病毒病是一组传染性神经退行性疾病，也称为传染性海绵状脑病。朊病毒疾病的分子机制还知之甚少。我们建议，以确定细胞因子，所需的朊病毒构象转换，并为随后获得的朊病毒构象的稳定是重要的。拟议研究的成功可能会为未来的药物发现和毁灭性朊病毒疾病的新疗法提供靶基因。

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.