Kaur Jaskirat, Roy Ipsita
Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India.
ACS Chem Neurosci. 2025 Jun 4;16(11):2024-2034. doi: 10.1021/acschemneuro.4c00865. Epub 2025 May 19.
Heat shock factor 1 (HSF1) orchestrates the cellular heat shock response (HSR) by binding to heat shock elements (HSEs) in the promoters of genes encoding heat shock proteins (HSPs). In a nonstressed state, HSF1 exists in a dormant complex with HSP90 and other chaperones. Upon cellular stress or upon inhibition of HSP90, HSF1 dissociates from the complex and activates the expression of HSPs to mitigate protein misfolding and aggregation. This study explores the potential of RNA aptamers selected against HSP90 to modulate HSF1 activity, with a role in Huntington's disease model characterized by protein aggregation. Selected aptamers disrupted the HSP90-HSF1 interaction, enhancing the binding of HSF1 with HSEs. This upregulated heat shock response (HSR) and reduced aggregation of Q74-huntingtin in Neuro 2a cells with improved cell survival. Designed antidote sequences could reverse the effect of the aptamers on the HSF1-HSE interaction, allowing for fine-tuning of HSR. Chronic activation of stress response pathways is deleterious for cellular fitness. Our findings suggest that coupling an antidote with an aptamer offers a novel therapeutic strategy to regulate cellular proteostasis under disease conditions.
热休克因子1（HSF1）通过与编码热休克蛋白（HSP）的基因启动子中的热休克元件（HSE）结合来协调细胞热休克反应（HSR）。在非应激状态下，HSF1与HSP90和其他伴侣蛋白形成休眠复合物存在。在细胞应激或HSP90受到抑制时，HSF1从复合物中解离并激活HSP的表达，以减轻蛋白质错误折叠和聚集。本研究探讨了针对HSP90筛选的RNA适体调节HSF1活性的潜力，其在以蛋白质聚集为特征的亨廷顿舞蹈病模型中发挥作用。筛选出的适体破坏了HSP90-HSF1相互作用，增强了HSF1与HSE的结合。这上调了热休克反应（HSR），并减少了Neuro 2a细胞中Q74-亨廷顿蛋白的聚集，提高了细胞存活率。设计的解毒序列可以逆转适体对HSF1-HSE相互作用的影响，从而实现对HSR的微调。应激反应途径的慢性激活对细胞健康有害。我们的研究结果表明，将解毒剂与适体结合提供了一种在疾病条件下调节细胞蛋白质稳态的新型治疗策略。
