Protein Phase Separation as a Stress Survival Strategy

Cells under stress must adjust their physiology, metabolism, and architecture to adapt to the new conditions. Most importantly, they must down-regulate general gene expression, but at the same time induce synthesis of stress-protective factors, such as molecular chaperones. Here, we investigate how the process of phase separation is used by cells to ensure adaptation to stress. We summarize recent findings and propose that the solubility of important translation factors is specifically affected by changes in physical-chemical parameters such temperature or pH and modulated by intrinsically disordered prion-like domains. These stress-triggered changes in protein solubility induce phase separation into condensates that regulate the activity of the translation factors and promote cellular fitness. Prion-like domains play important roles in this process as environmentally regulated stress sensors and modifier sequences that determine protein solubility and phase behavior. We propose that protein phase separation is an evolutionary conserved feature of proteins that cells harness to regulate adaptive stress responses and ensure survival in extreme environmental conditions.