Pleiotropic functions of glutathione in the adaptive response to long-term nitrogen starvation in Escherichia coli

Nitrogen (N) is essential for bacterial growth, and adaptation to N starvation involves extensive reprogramming of gene expression. A hallmark subcellular feature in long-term N starved Escherichia coli cells is the presence of biomolecular condensates of the major bacterial RNA regulator Hfq. The Hfq condensates, which accumulate gradually during N starvation, contribute to adaptation by modulating RNA metabolism and central metabolic pathways. Metabolites play central roles in stress responses, often acting as modulators of protein function to support survival and recovery. Glutathione (GSH), a universal stress protectant, has broad roles in bacterial stress adaptation, yet its function during N starvation remains unexplored. Using a GSH-deficient mutant (DeltagshAB), we show that GSH is required for optimal survival and recovery from prolonged N starvation. We reveal that GSH regulates the temporal dynamics of Hfq condensation and dissipation during starvation and recovery, respectively, via an as-yet unknown mechanism. Notably, these two functions of GSH appear mutually exclusive, highlighting its pleiotropic role in the adaptive response to N starvation that potentially extends its canonical function as a stress protectant.