Phase separation as a survival strategy: stress protection by translation factor condensates

• Applicant: Professor Dr. Simon Alberti
• Subject Area: Biochemistry ; Biophysics ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 471025906

The concept of protein condensation provides a novel way to think about how cells sense stress and mount an appropriate response for survival. Work so far has barely touched the surface of this novel principle and we have yet to learn of the contributions it can make to understanding stress responses and the evolution and ecology of organisms. We recently showed that the yeast translation factor Ded1p assembles into condensates in response to heat stress. This inactivates its helicase activity thereby promoting a switch in translation from housekeeping to stress protein production. However, important questions remain unanswered: what are the molecular events underlying heat-induced condensation by Ded1p and what are the specific physiological benefits? Is the condensation of translation factors crucial for regulating translation during heat stress? And if so, which other translation factors besides Ded1p assemble by heat-induced condensation? Recent evidence suggests that Ded1p interacts with the translation initiation complex eIF4F during translation initiation. Like for Ded1p, we have found that eIF4F assembles into condensates in a heat-dependent manner. We hypothesize that eIF4F inactivation by condensation promotes an additional switch in translation which serves to downregulate specific sets of mRNAs. The purpose of the work program is therefore to uncover the molecular events underlying the formation of heat-induced condensates by Ded1p and eIF4F and to pinpoint the adaptive functions that are associated with condensation. More specifically, we will 1) study the molecular events underlying heat-induced condensation, 2) determine critical amino acid motifs underlying thermal sensitivity and analyze how evolution has tuned protein condensation to different thermal environments, 3) study how condensate assembly and disassembly is regulated and how condensate dynamics and properties affect the stress response, and 4) establish the physiological function of translation factor condensates and determine how condensation promotes stress survival. We envisage that this research project will provide a much-needed deeper molecular understanding of heat-induced condensation, thus providing a template for temperature regulation of other fundamental cellular processes such as transcription and signaling.

• DFG Programme: Research Grants