Department of Biology, Stanford University, Stanford, California 94305, USA.
J Biol Chem. 2013 Aug 16;288(33):23633-8. doi: 10.1074/jbc.C113.481945. Epub 2013 Jul 9.
The cellular heat shock response (HSR) protects cells from toxicity associated with defective protein folding, and this pathway is widely viewed as a potential pharmacological target to treat neurodegenerative diseases linked to protein aggregation. Here we show that the HSR is not activated by mutant huntingtin (HTT) even in cells selected for the highest expression levels and for the presence of inclusion bodies containing aggregated protein. Surprisingly, HSR activation by HSF1 overexpression or by administration of a small molecule activator lowers the concentration threshold at which HTT forms inclusion bodies in cells expressing aggregation-prone, polyglutamine-expanded fragments of HTT. These data suggest that the HSR does not mitigate inclusion body formation.
细胞热休克反应（HSR）可保护细胞免受与错误折叠蛋白相关的毒性，该途径被广泛认为是治疗与蛋白聚集相关的神经退行性疾病的潜在药物靶点。在这里，我们发现即使在选择表达水平最高且存在包含聚集蛋白的包涵体的细胞中，突变型亨廷顿蛋白（HTT）也不会激活 HSR。令人惊讶的是，通过 HSF1 过表达或施用小分子激活剂激活 HSR 会降低 HTT 在表达易聚集、多聚谷氨酰胺扩展 HTT 片段的细胞中形成包涵体的浓度阈值。这些数据表明 HSR 不能减轻包涵体的形成。
