Metabolic principles of stress granule formation

Stress Granules (SG) are cytoplasmic aggregates that form by Liquid Liquid Phase Separation (LLPS). They harbor RNAs and RNA-binding proteins, and may serve as storage centers during different types of cellular stress. Emerging themes show that they can form in chemotherapy-stressed cancer cells or during neurodegenerative pathologies, and that their biophysical properties can differ depending on the stress inducer. In this study, we show how metabolite starvation, along with disruption of the cytoskeleton, can entirely inhibit SG formation under regular stress conditions. Interestingly, we find that the addition of a single metabolite can rescue the formation SGs under stress. Moreover, we revealed that the rescued SGs are different from SGs that form under regular stress conditions; they harbor different factors, are activated by different kinases of the stress induced pathway and are more sensitive to other treatments. We also found that these principles of nutrient deprivation and cytoskeletal integrity apply to various SG inducers. Our study suggests that SGs are in fact a family of closely related structures displaying heterogeneity in composition that is dependent on the type of stress induced.