Promiscuity of response regulators for thioredoxin steers bacterial virulence

Abstract

The exquisite specificity between a sensor kinase and its cognate response regulator ensures faithful partner selectivity within two-component pairs concurrently firing in a single bacterium, minimizing crosstalk with other members of this conserved family of paralogous proteins. We show that conserved hydrophobic and charged residues on the surface of thioredoxin serve as a docking station for structurally diverse response regulators. Using the OmpR protein, we identify residues in the flexible linker and the C-terminal β-hairpin that enable associations of this archetypical response regulator with thioredoxin, but are dispensable for interactions of this transcription factor to its cognate sensor kinase EnvZ, DNA or RNA polymerase. Here we show that the promiscuous interactions of response regulators with thioredoxin foster the flow of information through otherwise highly dedicated two-component signaling systems, thereby enabling both the transcription of Salmonella pathogenicity island-2 genes as well as growth of this intracellular bacterium in macrophages and mice.

The methylglyoxal pathway is a sink for glutathione in Salmonella experiencing oxidative stress

“…Reactive oxygen species engendered in the respiratory burst of professional phagocytes through the activity of phagocyte NADPH oxidase enzymatic complexes damage cysteine and methionine residues, metal prosthetic groups, and DNA molecules [9]. Salmonella adapt to the antimicrobial activity of the phagocyte NADPH oxidase by engaging the vacuolar-remodeling actions of the Salmonella pathogenicity island-2 type III secretion system, the detoxifying activities of superoxide dismutases, catalases and hydroperoxidases, the nucleic acid-repairing actions of DNA recombination systems, and the chaperoning features of thioredoxin [10][11][12][13][14][15][16][17][18][19].…”