Abstract：
The transcription factor HSF-1 (heat shock factor 1) acts as a master regulator of heat shock response in eukaryotic cells to maintain cellular proteostasis. The protein has a protective role in preventing cells from undergoing ageing, and neurodegeneration, and also mediates tumorigenesis. Thus, modulating HSF-1 activity in humans has a promising therapeutic potential for treating these pathologies. Loss of HSF-1 function is usually associated with impaired stress tolerance. Contrary to this conventional knowledge, we show here that inactivation of HSF-1 in the nematode Caenorhabditis elegans results in increased thermotolerance at young adult stages, whereas HSF-1 deficiency in animals passing early adult stages indeed leads to decreased thermotolerance, as compared to wild-type. Furthermore, a gene expression analysis supports that in young adults, distinct cellular stress response and immunity-related signaling pathways become induced upon HSF-1 deficiency. We also demonstrate that increased tolerance to proteotoxic stress in HSF-1-depleted young worms requires the activity of the unfolded protein response of the endoplasmic reticulum and the SKN-1/Nrf2-mediated oxidative stress response pathway, as well as an innate immunity-related pathway, suggesting a mutual compensatory interaction between HSF-1 and these conserved stress response systems. A similar compensatory molecular network is likely to also operate in higher animal taxa, raising the possibility of an unexpected outcome when HSF-1 activity is manipulated in humans.
摘要：
转录因子HSF-1（热休克因子1）充当真核细胞中热休克反应的主要调节因子，以维持细胞的蛋白质平衡。这种蛋白质在防止细胞老化方面具有保护作用，和神经变性，并介导肿瘤发生。因此，在人类中调节HSF-1活性对于治疗这些病症具有有希望的治疗潜力。HSF-1功能的丧失通常与应激耐受性受损有关。与传统知识相反,我们在这里表明，线虫秀丽隐杆线虫中HSF-1的失活导致年轻成年阶段的耐热性增加，而在成年早期的动物中HSF-1缺乏确实会导致耐热性下降，与野生型相比。此外，基因表达分析支持年轻人，HSF-1缺乏会诱导不同的细胞应激反应和免疫相关信号通路。我们还证明，在HSF-1耗尽的幼虫中，对蛋白毒性应激的耐受性增加需要内质网和SKN-1/Nrf2介导的氧化应激反应途径的未折叠蛋白反应的活性。以及与先天免疫相关的途径，表明HSF-1与这些保守的应激反应系统之间存在相互补偿的相互作用。类似的补偿性分子网络也可能在高等动物类群中运作，当在人类中操纵HSF-1活性时，增加了意外结果的可能性。
