A novel copper-sensing two-component system for inducing Dsb gene expression in bacteria

In nature,bacteria must sense copper and tightly regulate gene expression to evade copper toxicity.Here,we identify a new copper-responsive two-component system named DsbRS in the important human pathogen Pseudomonas aeruginosa;in this system,DsbS is a sensor histidine kinase,and DsbR,its cognate response regulator,directly induces the transcription of genes involved in protein disulfide bond forma-tion (Dsb) (i.e.,the dsbDEG operon and dsbB).In the absence of copper,DsbS acts as a phosphatase toward DsbR,thus blocking the transcription of Dsb genes.In the presence of copper,the metal ion directly binds to the sensor domain of DsbS,and the Cys82 residue plays a critical role in this process.The copper-binding behavior appears to inhibit the phosphatase activity of DsbS,leading to the activation of DsbR.The copper resistance of the dsbRS knock-out mutant is restored by the ectopic expression of the dsbDEG operon,which is a DsbRS major target.Strikingly,cognates of the dsbRS-dsbDEG pair are widely distributed across eubacteria.In addition,a DsbR-binding site,which contains the consensus sequence 5'-TTA-Ns-TTAA-3',is detected in the promoter region of dsbDEG homologs in these species.These findings suggest that the regulation of Dsb genes by DsbRS represents a novel mechanism by which bacterial cells cope with copper stress.