Control of Redox Balance by the Stringent Response Regulatory Protein Promotes Antioxidant Defenses of Salmonella

• Published in: The Journal of biological chemistry Vol. 285; no. 47; pp. 36785 - 36793
• Main Authors: Henard, Calvin A., Bourret, Travis J., Song, Miryoung, Vázquez-Torres, Andrés
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.11.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Antioxidant; Antioxidants - metabolism; Bacteria; Bacterial Metabolism; Bacterial Proteins - metabolism; beta-Galactosidase - metabolism; Genes, Suppressor; Glucose-6-Phosphate - metabolism; Glucosephosphate Dehydrogenase - metabolism; Glutathione - metabolism; Hydrogen Peroxide - pharmacology; Macrophage; Macrophages - cytology; Macrophages - metabolism; Membrane Glycoproteins - physiology; Metabolic Regulation; Mice; Mice, Inbred C57BL; Microbiology; NADPH Oxidase 2; NADPH Oxidases - metabolism; NADPH Oxidases - physiology; Oxidation-Reduction; Oxidative Stress; Pentose Pathway; Phagocytes - metabolism; Reactive Oxygen Species; Reactive Oxygen Species - metabolism; Respiratory Burst; Salmonella; Salmonella Infections - immunology; Salmonella Infections - metabolism; Salmonella Infections - virology; Salmonella typhimurium - metabolism; Salmonella typhimurium - pathogenicity; Tricarboxylic Acid Cycle; Virulence; Reactive Oxygen Species; Oxidative Stress; Bacterial Metabolism; Respiratory Burst; Metabolic Regulation; Pentose Pathway; Tricarboxylic Acid Cycle; Bacteria; Antioxidant; Macrophage
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.160960

We report herein a critical role for the stringent response regulatory DnaK suppressor protein (DksA) in the coordination of antioxidant defenses. DksA helps fine-tune the expression of glutathione biosynthetic genes and discrete steps in the pentose phosphate pathway and tricarboxylic acid cycle that are associated with the generation of reducing power. Control of NAD(P)H/NAD(P)+ redox balance by DksA fuels downstream antioxidant enzymatic systems in nutritionally starving Salmonella. Conditional expression of the glucose-6-phosphate dehydrogenase-encoding gene zwf, shown here to be under DksA control, increases both the NADPH pool and antioxidant defenses of dksA mutant Salmonella. The DksA-mediated coordination of redox balance boosts the antioxidant defenses of stationary phase bacteria. Not only does DksA increase resistance of Salmonella against hydrogen peroxide (H2O2), but it also promotes fitness of this intracellular pathogen when exposed to oxyradicals produced by the NADPH phagocyte oxidase in an acute model of infection. Given the role of DksA in the adjustment of gene expression in most bacteria undergoing nutritional deprivation, our findings raise the possibility that the control of central metabolic pathways by this regulatory protein maintains redox homeostasis essential for antioxidant defenses in phylogenetically diverse bacterial species.