Rescue of transcriptional pausing in metabolic genes jumpstarts Salmonella antioxidant defenses

Abstract

ABSTRACTDetoxification, scavenging and repair systems embody the archetypical antioxidant defenses of prokaryotic and eukaryotic cells1–3. Metabolic rewiring is an emergent aspect in the adaptation of bacteria to oxidative stress4, 5. Evolutionarily diverse bacteria combat the toxicity of reactive oxygen species by actively engaging the stringent response6–8, a metabolic program activated at the level of transcription initiation via guanosine tetraphosphate and the α-helical DksA protein9. Studies herein with Salmonella demonstrate that the interactions of structurally related, but functionally unique, α-helical Gre factors with the secondary channel of RNA polymerase elicit the expression of metabolic signatures that are associated with resistance to oxidative killing. Gre proteins resolve pauses in ternary elongation complexes of Embden-Meyerhof-Parnas (EMP) glycolysis and aerobic respiration genes. The Gre-directed utilization of glucose in overflow and aerobic metabolism satisfies the energetic and redox demands of Salmonella, while preventing the occurrence of amino acid bradytrophies. Moreover, the simultaneous utilization of lower glycolysis, the methylglyoxal pathway and the electron transport chain curtails the noxious coexistence of reductive and electrophilic stress. The resolution of transcriptional pauses in EMP glycolysis and aerobic respiration genes by Gre factors safeguards Salmonella from the cytotoxicity of phagocyte NADPH oxidase in the innate host response. Control of transcriptional elongation represents a pivotal breakpoint in the regulation of metabolic programs underlying bacterial pathogenesis.