Function and Regulation of Stress-Induced Adaptive Condensates

项目摘要 在我们对真核生物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，热休克一直被认为是一种蛋白毒性应激，会触发 变性蛋白，必须被诱导的热休克蛋白清除。我们小组的最新结果 其他人则建立了一种互补的范式：温度充当生理信号，触发 具有特定细胞功能的生物分子凝聚体的适应性形成，以及凝聚 这一过程受热休克蛋白的调节。至关重要的是，在蛋白质毒性模型中，聚集体是垃圾，但在 自适应冷凝模型，它们是功能瑰宝。使用一套完整的生化，细胞生物学， 在过去的十年中，我们正在寻求三个相互关联的领域：1)确定 并剖析了特定的热休克和应激诱导的蛋白质凝聚体的细胞功能。 Mrna；2)研究凝聚和扩散的调节，重点研究生理的特异性。 凝析油及其重塑和应激诱导的分子伴侣逆转；以及3)探测 依赖温血寄主的真菌对温度的感知和向适应性反应的转导 用于脊椎动物免疫系统中细胞的生长或扩散，以及依赖于温度的激活 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，这些 研究有望阐明已知的细胞内聚集过程在 神经退行性疾病，发现控制真菌的新机制，并提供新的分子洞察力 了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.