Chronic starvation induces noncanonical pro-death stress granules

Stress granules (SGs) assemble under stress-induced conditions that inhibit protein synthesis, including phosphorylation of eIF2 alpha, inhibition of the RNA helicase eIF4a proteins or inactivation of mTORC1. Classically defined SGs are composed of translation initiation factors, 40S ribosomes, RNA-binding proteins and poly(A)(+) mRNAs. As such, they represent an important compartment for storage of mRNAs and regulation of their translation. Emerging work on SGs indicates that these structures might promote cellular survival in diverse disease states. Yet, much work on SG formation and function employs acute stress conditions, which might not accurately reflect the chronic stresses that manifest in human disease. Here, we used prolonged nutrient starvation to model and investigate SG formation and function during chronic stress in a human cell line and mouse embryonic fibroblasts. Surprisingly, we found that SGs that form under chronic nutrient starvation lack 40S ribosomes, do not actively exchange their constituent components with cytoplasmic pools and promote cell death. We named these SGs starvation-induced SGs (stSGs). Our results on stSGs imply that SG assembly and function in the context of prolonged nutrient starvation stress differ significantly from what has been described for acute stress conditions.