Extracellular redox sensors control the protein secretion stress response in Streptomyces

Translocating unfolded polypeptides across membranes is essential in all domains of life and in bacteria requires the conserved Sec machinery and ATP. Bacterial Sec substrates fold outside the cell and often use DsbA-catalysed disulfide bond formation between cysteines to ensure correct folding. Extracellular protein misfolding triggers a stress response that involves production of dual function HtrA-family chaperone/proteases. In Gram-negative bacteria this is called the envelope stress response and in Gram-positive bacteria the secretion stress response, but the exact signals sensed by bacteria to trigger these stress responses are not well understood. In Streptomyces bacteria the secretion stress response is mediated by the CutRS and CssRS two-component systems which control the levels of four conserved HtrA-family chaperones. Here we show that the CutS sensor kinase contains two conserved cysteine residues in its extracellular sensor domain that control CutS activity. CssS also has two conserved and invariant cysteines in its sensor domain, and we propose that CutS and CssS detect the extracellular redox state and work together to ensure secreted proteins fold correctly in the fluctuating soil environment. Further analysis of ∼12,800 genomes indicated that 98.9% of strains across all bacterial classes have at least one sensor kinase with two or more extracellular cysteine residues, suggesting that extracellular redox sensing by two-component systems is widespread in bacteria.