Function and Regulation of Stress-Induced Adaptive Condensates

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.