The Collapse of Proteostasis during Aging is Mediated by Cytoskeletal Actin Functions

热休克转录因子-1（HSF-1）是一种保守的转录因子，对细胞的抗逆能力和寿命至关重要 保持战略定力HSF-1的典型功能是调节编码分子生物学功能的基因网络。 保护蛋白质免受外在环境压力或内在年龄相关性损伤的分子伴侣 恶化在秀丽隐杆线虫中，我们发现了一种改良的HSF-1菌株， 抗性和寿命而没有增强的伴侣蛋白诱导。有趣的是，修饰的HSF-1和野生型HSF-1都是 而HSF-1型则能够增加一系列肌动蛋白调节基因的表达。这些数据 表明HSF-1在肌动蛋白细胞骨架完整性中具有显著作用。 令人惊讶的是，这些肌动蛋白组分中至少一种的上调单独足以增加应激 抵抗力和寿命。我们假设，在衰老过程中，肌动蛋白稳态的丧失发生， 这种损失是由于HSF-1不能正常地产生反应以保护肌动蛋白免受压力的影响， 老化细胞在这个建议中，我们将探讨如何肌动蛋白稳态成为妥协，在正常的 衰老，以及HSF-1的活性是否会保护细胞免受年龄发作的功能下降。我们将使用 最先进的体内成像技术以及创新的生化分析，以监测 肌动蛋白结构和动态的空间和时间。我们预测，在老年人中， 动物将恢复肌动蛋白细胞骨架的功能，保护细胞免受年龄损伤， 延长寿命我们将进一步探讨hsf-1作为一个团队的一部分工作的可能性， 应激反应蛋白被设计来管理“肌动蛋白细胞骨架应激反应”， 随着年龄的增长，并提出了一系列的遗传筛选，以确定其他肌动蛋白调节因子。最后我们将 探索肌动蛋白动力学的变化必须在组织和细胞之间协调的想法，这表明 HSF-1在肌动蛋白动力学的内分泌介导调节中的作用。我们将把这项工作与一个新发现的 了解肌动蛋白稳态在老年人中看到的许多破坏性疾病中的作用， 个体

The conserved heat shock transcription factor-1 (HSF-1) is essential to cellular stress resistance and life-span determination. The canonical function of HSF-1 is to regulate a network of genes encoding molecular chaperones that protect proteins from damage caused by extrinsic environmental stress or intrinsic age-related deterioration. In Caenorhabditis elegans, we discovered a modified HSF-1 strain that increased stress resistance and longevity without enhanced chaperone induction. Intriguingly, both modified HSF-1 and wild type HSF-1 were instead capable of increasing expression of an array of actin regulating genes. These data suggest that HSF-1 has a prominent role in actin cytoskeletal integrity. Surpassingly, upregulation of at least one of these actin components was alone sufficient to increase stress resistance and life span. We hypothesize that a loss in actin homeostasis occurs during the aging process, and that this loss is driven by the inability for HSF-1 to normally mount a response to protect actin from stress in aging cells. In this proposal, we will explore how actin homeostasis becomes compromised during normal aging, and whether the activity of HSF-1 will protect the cells from age-onset declines in function. We will use state-of-the-art, in vivo imaging techniques alongside innovative biochemical analyses to monitor changes in actin structure and dynamics both spatial and temporally. We predict that forced expression of hsf-1 in geriatric animals will restore the function of the actin cytoskeleton, protecting the cell from age-onset damage and extending lifespan. We will further explore the possibility that hsf-1 works as a part of a team of additional stress-responsive proteins designed to manage a “actin cytoskeletal stress response” that be compromised with age, and propose a series of genetic screens to identify other actin-regulatory factors. Finally, we will explore the idea that changes in actin dynamics must be coordinated across tissues and cells, suggesting a role for hsf-1 in the endocrine mediated regulation of actin dynamics. We will leave this work with a newfound understanding of the role of actin homeostasis plays in many of the destructive diseases seen in older individuals.