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.

Liang Yu;Qiao Cao;Weizhong Chen;Nana Yang;Cai-Guang Yang;Quanjiang Ji;Min Wu;Taeok Bae;Lefu Lan

University of Chinese Academy of Sciences,Beijing 100049,China;State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;School of Physical Science and Technology,ShanghaiTech University,Shanghai 201210,China;School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China;Department of Biomedical Sciences,University of North Dakota,Grand Forks ND 58203-9037,USA;Department of Microbiology and Immunology,Indiana University School of Medicine-Northwest,Gary IN 46408,USA;NMPA Key Laboratory for Testing Technology of Pharmaceutical Microbiology,Shanghai Institute for Food and Drug Control,Shanghai 201203,China

科学通报（英文版）

[1]Liang Yu;Qiao Cao;Weizhong Chen;Nana Yang;Cai-Guang Yang;Quanjiang Ji;Min Wu;Taeok Bae;Lefu Lan-.A novel copper-sensing two-component system for inducing Dsb gene expression in bacteria)[J].科学通报（英文版）,2022(02):198-212

Dsb,DsbRS,DsbS,DsbR,dsbDEG,dsbB,Cys82,dsbRS,cognates,eubacteria,TTAA

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