PKA-dependent phosphorylation drives stress granule maturation and controls recovery from prolonged starvation

During environmental stress, cells form dynamic biomolecular condensates called stress granules (SGs) that can undergo a maturation process towards more solid-like material states. Deposition of SG proteins in insoluble aggregates is a hallmark of neurodegenerative pathologies, provoking inquiry into the pathological link and mechanisms underlying SG maturation. Here we show that yeast SGs mature into a solid-like state during long-term stationary phase driven by protein kinase A (PKA)-dependent phosphorylation of the SG proteome. Catalytic PKA subunits condense in SGs upon stationary phase where SG-localized PKA activity is maintained. PKA phosphorylates key SG components, including the pyruvate kinase Cdc19, which is necessary and sufficient for Cdc19 maturation into amyloid-like structures. Inhibiting PKA during long-term stationary phase prevents SG maturation, which alters metabolism and delays ordered re-start of cell growth after re-feeding. These results describe a SG maturation mechanism selectively activated during chronic stress that preserves SG integrity and promotes cell survival.