Activation of the heat shock response by sulfhydryl-reactive chemoprotective agents

背景：蛋白质稳态紊乱是伴随衰老和年龄相关病理的复杂生物过程的主要因素，也发生在应激条件下。为了保护蛋白质组，真核生物进化出了高效的机制。最突出的是分别由转录因子热休克因子1 （HSF1）和核因子-红细胞2相关因子2 （Nrf2）控制的热休克反应和2期反应。人们对这些系统的小分子诱导剂的发现和开发越来越感兴趣，这些系统用于预防和治疗与衰老相关的慢性退行性疾病。热休克反应和第二阶段反应的诱导导致细胞保护蛋白网络的上调，该网络检测并抵消热、氧化和亲电应激的潜在有害后果，并促进存活。此外，这两种途径都参与多种相互作用，将稳态代谢与应激生物学联系起来，并最终在决定健康和寿命方面发挥关键作用。Nrf2的小分子活化剂有一个共同的化学特征，即巯基反应性。新出现的证据表明，巯基反应性分子也能激活热休克反应。奇怪的是，抗炎活性是Nrf2诱导剂的一贯特性，这表明抑制炎症是其化学保护作用的核心方面。然而，这个性质只是部分依赖于nrf2。有趣的是，HSF1的激活具有抗炎作用，并且需要在炎症反应中提供保护。目的和目的：我们假设巯基反应性化学保护剂的细胞保护和抗炎活性是通过激活两种不同的转录因子Nrf2和HSF1，通过一个共同的化学信号，即巯基反应性来介导的。拟建研究的具体目的是：1。确定哪类巯基反应性化学保护剂上调hsf1介导的基因表达。阐明巯基反应性在转录因子HSF1.3活化中的重要性。明确转录因子HSF1和Nrf2在抗促炎刺激中的相对作用。潜在的应用和好处：慢性退行性疾病对我们社会的负担预计将继续增加，主要是由于人口老龄化。尽管目前还没有令人满意的解决方案，但考虑利用细胞固有的细胞保护机制实施预防措施是及时的。利用小分子的能力（其中许多存在于人类饮食中，因此被认为是低毒性的）来上调细胞内防御，是未来发展的一个令人兴奋的领域。如果氧化还原调节和转录因子半胱氨酸修饰是2期反应和热休克反应的核心，那么这种“双重”激活剂的开发将是同时操纵这些途径并实现协同保护作用的理想选择。

Context: Disturbances in the protein homeostasis are major contributors to the complex biological processes that accompany ageing and age-associated pathologies, and also occur during conditions of stress. To protect the proteome, eukaryotic organisms have evolved highly efficient mechanisms. Most prominent are the heat shock response and the phase 2 response that are controlled by transcription factors heat shock factor 1 (HSF1) and nuclear factor-erythroid 2-related factor 2 (Nrf2), respectively. There is a growing interest in the discovery and development of small molecule-inducers of these systems for prevention and treatment of chronic degenerative conditions associated with ageing. Induction of the heat shock response and the phase 2 response leads to upregulation of large networks of cytoprotective proteins that detect and counteract the potentially deleterious consequences of thermal, oxidative and electrophilic stress, and promote survival. Furthermore, both pathways are involved in multiple interactions that link homeostatic metabolism with stress biology, and ultimately play crucial roles in determining health and life span. Small molecule activators of Nrf2 have a common chemical signature, that of sulfhydryl reactivity. Emerging evidence suggests that sulfhydryl-reactive molecules also activate the heat shock response. Curiously, anti-inflammatory activity is a consistent property of Nrf2 inducers, indicating that suppression of inflammation is a central aspect of their chemoprotective actions. However, this property is only partially Nrf2-dependent. Interestingly, HSF1 activation has anti-inflammatory effects and is required for protection during inflammatory responses. Aims and Objectives: We hypothesize that the cytoprotective and anti-inflammatory activities of sulfhydryl-reactive chemoprotective agents are mediated through activation of two distinct transcription factors, i.e., Nrf2 and HSF1, through a common chemical signal, that of sulfhydryl reactivity. The specific aims of the proposed study are:1. To establish which classes of sulfhydryl-reactive chemoprotective agents upregulate HSF1-mediated gene expression.2. To elucidate the importance of sulfhydryl reactivity in the activation of transcription factor HSF1.3. To define the relative roles of transcription factors HSF1 and Nrf2 in protection against pro-inflammatory stimuli.Potential applications and benefits: The burden of chronic degenerative conditions on our society is expected to continue to increase, largely due to ageing of the population. Whereas no satisfactory solutions are yet available, it is timely to think about implementing prevention measures that harness the intrinsic cytoprotective mechanisms of the cell. Exploiting the ability of small molecules, many of which are present in the human diet and therefore of presumed low toxicity, to upregulate intracellular defenses, is an exciting area for future development. If, as hypothesized, redox regulation and transcription factor cysteine modifications are central to both the phase 2 response and heat shock response, the development of such "dual" activators will be ideal for simultaneously manipulating these pathways and achieving synergistic protective effects.