Regulatory mechanisms of the Hsp90 chaperone machinery

Hsp90 伴侣机制的调节机制

• 批准号: 10319559
• 负责人: Mehdi Mollapour
• 金额: $ 40.45万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10319559
• 关键词: ATP phosphohydrolase; Autoimmune; Binding; Biochemical; Biological Assay; Biophysics; Cells; Client; Clinical Trials; Complex; Coupled; Disease; Goals; HSP 90 inhibition; Heat-Shock Proteins 90; Inflammatory; Knowledge; Malignant Neoplasms; Molecular; Molecular Chaperones; Nerve Degeneration; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Proteins; Regulation; Signal Transduction; Signal Transduction Pathway; TSC1 gene; Ubiquitination; Vision; Work; base; chaperone machinery; drug sensitivity; enhancing factor; inhibitor; preclinical study; proteostasis; targeted treatment

PROJECT SUMMARY The molecular chaperone Heat Shock Protein-90 (Hsp90) is essential for the folding and activity of an array of `client' proteins involved in signal transduction pathways. They are also responsible for many maladies including cancer, neurodegenerative, autoimmune and inflammatory diseases. Hsp90 inhibition strategies are currently being explored in these diseases in pre-clinical studies and clinical trials, however the optimal use of Hsp90-targeted therapeutics remains unknown. This is partly due to our limited knowledge of Hsp90 regulation in cells. Unraveling the detailed regulatory mechanisms of Hsp90 function in cells can provide new strategies to increase the cellular potency of Hsp90 inhibitors. Hsp90 chaperone function is coupled to its ATPase activity, which is regulated by co-chaperones and posttranslational modifications (PTMs). However, it is unclear how these regulatory components work together to fine tune Hsp90 function and also contribute towards drug sensitivity. During the past five years we have made major contributions towards the understanding of Hsp90 regulation by co-chaperones and PTMs. i) New co-chaperones: We have identified three new co-chaperones, FNIP1, 2 (collectively FNIPs) and Tsc1, that decelerate the chaperone cycle and facilitate chaper- oning of both kinase and non-kinase clients. They are regulated by PTMs (phosphoryla- tion, O-GlcNAcylation, SUMOlyation and ubiquitination). Their expression also enhances Hsp90 binding to drugs and consequently sensitizes cells to Hsp90 inhibitors. ii) Post- translational modification of Hsp90: Our work during the past decade on Hsp90 PTMs has redefined the regulation of its chaperone activity and revealed the reciprocal regula- tory mechanisms between client proteins, co-chaperones, and Hsp90. We have recently shown that loss of TSC1 co-chaperone leads to hypoacetylation of Hsp90 and elevated its ATPase activity. It also subsequently decreased Hsp90 binding to its inhibitors. Our long-term goal is to unravel the molecular mechanism of Hsp90 chaperone regulation in cells and regulatory factors enhancing cellular potency of Hsp90 inhibitors. Our strategy is to use biochemical, biophysical and cell-based assays to decipher the interconnectivi- ty and compensatory mechanisms between the co-chaperones and PTMs. Our vision is to utilize this information to dissect the intricate network of regulatory signals involved in fine tuning Hsp90 function and their impact towards cellular sensitivity to Hsp90 inhibi- tors.

项目摘要 分子伴侣热激蛋白-90（HSP90）对于折叠和 参与信号转导途径的一系列“客户端”蛋白的活性。他们是 还负责许多疾病，包括癌症，神经退行性，自身免疫性 和炎症性疾病。 HSP90抑制策略目前正在探索 这些疾病在临床前研究和临床试验中，但是 HSP90靶向的治疗剂仍然未知。这部分是由于我们有限的 细胞中HSP90调控的知识。阐明详细的调节机制 细胞中HSP90功能的功能可以提供新的策略，以提高细胞效力 HSP90抑制剂。 HSP90伴侣功能与其ATPase活性耦合，即 由联合伴侣和翻译后修饰（PTMS）调节。但是，是 尚不清楚这些调节组件如何一起使用以微调HSP90功能和 也有助于药物敏感性。在过去的五年中，我们做了专业 共同伴侣对HSP90监管的理解和 PTMS。 i）新的联合伴侣：我们已经确定了三个新的联合伴侣，FNIP1，2 （统称FNIP）和TSC1，减速伴侣周期并促进伴侣 激酶和非激酶客户群的启动。它们受PTM的调节（Phosphoryla- tion，o-glcnacylation，sumolotion和泛素化）。他们的表达也增强了 HSP90与药物结合，因此使细胞对HSP90抑制剂敏感。 ii） HSP90的翻译修改：我们过去十年在HSP90 PTMS上的工作 已经重新定义了其伴侣活性的调节，并揭示了相互调节 客户蛋白，共伴侣和HSP90之间的保守机制。我们最近有 表明TSC1副酮的丧失导致HSP90的低乙酰化和升高 它的ATPase活性。随后，它还降低了HSP90与其抑制剂的结合。我们的 长期目标是阐明Hsp90伴侣调节的分子机制 细胞和调节因素增强了HSP90抑制剂的细胞效力。我们的策略 是使用生化，生物物理和基于细胞的测定法来破译互连。 共同伴侣和PTM之间的TY和代偿机制。我们的愿景是 利用这些信息来剖析涉及的调节信号的复杂网络 微调HSP90功能及其对细胞对HSP90抑制的敏感性的影响 TOR。