Function and Regulation of Stress-Induced Adaptive Condensates

项目摘要 在我们对真核热休克反应的理解中，一场概念和经验的革命正在发生。 长期以来，热休克被认为是一种蛋白毒性应激，其触发蛋白质的毒性聚集体的形成。 变性蛋白，这必须通过诱导热休克蛋白来清除。我们小组的最新结果 和其他人已经建立了一个互补的范例：温度作为生理信号，触发 具有特定细胞功能的生物分子缩合物的适应性形成，以及缩合 这一过程由热休克蛋白调控。至关重要的是，在蛋白毒性模型中，聚集体是垃圾，但在 自适应凝聚模型，它们是功能的瑰宝。使用一套完整的生化，细胞生物， 在过去十年中建立的渐进式方法中，我们正在三个相互关联的领域开展工作：1）确定 剖析特定的热休克和应激诱导的蛋白质浓缩物的细胞功能， 2）研究蛋白质的凝聚和分散的调节，重点研究蛋白质的生理特性， 缩合物和它们的重塑和逆转的压力诱导的分子伴侣;和3）探测 依赖于温血宿主真菌的温度感觉和适应性反应的传导 用于生长或扩散，以及脊椎动物免疫系统中细胞的温度依赖性活化 在发烧的时候除了对真核细胞的运作和组织的基本见解外， 研究有望揭示已知在细胞内聚集过程中失调的细胞内聚集过程， 神经退行性疾病，揭示控制真菌的新机制，并提供新的分子见解 发烧是如何促进免疫细胞激活的。

Project Summary A conceptual and empirical revolution is occurring in our understanding of the eukaryotic heat-shock response. Heat shock has long been conceived of as a proteotoxic stress, triggering formation of toxic aggregates of denatured proteins, which must be cleaned up by induced heat shock proteins. Recent results from our group and others have established a complementary paradigm: temperature acts as a physiological signal, triggering the adaptive formation of biomolecular condensates with specific cellular functions, and the condensation process is regulated by heat shock proteins. Crucially, in the proteotoxic model, aggregates are trash, but in the adaptive condensation model, they are functional treasure. Using an integrated set of biochemical, cell biological, and evolutionary approaches established over the past decade, we are pursuing three linked areas: 1) identifying and dissecting the cellular functions of particular heat-shock and stress-induced condensates of protein and mRNA; 2) studying the regulation of condensation and dispersal, focusing on the specificity of physiological condensates and their remodeling and reversal by stress-induced molecular chaperones; and 3) probing the sensation and transduction of temperature into adaptive responses in fungi which rely on warm-blooded hosts for growth or dispersal, and in the temperature-dependent activation of cells in the vertebrate immune system during fever. In addition to fundamental insights into the operation and organization of eukaryotic cells, these studies promise to shed light on intracellular aggregation processes known to be dysregulated during neurodegenerative disease, uncover new mechanisms for the control of fungi, and provide new molecular insight into how fever promotes immune-cell activation.