CpxR/CpxA Controls scsABCD Transcription To Counteract Copper and Oxidative Stress in Salmonella enterica Serovar Typhimurium.

Periplasmic thiol/disulfide oxidoreductases participate in the formation and isomerization of disulfide bonds and contribute to the virulence of pathogenic microorganisms. Among the systems encoded in the Salmonella genome, the system encoded by the scsABCD locus was shown to be required to cope with Cu and H2O2 stress. Here we report that this locus forms an operon whose transcription is driven by a promoter upstream of scsA and depends on CpxR/CpxA and on Cu. Furthermore, genes homologous to scsB, scsC, and scsD are always detected immediately downstream of scsA and in the same genetic arrangement in all scsA-harboring enterobacterial species. Also, a CpxR-binding site is detected upstream of scsA in most of those species, providing evidence of evolutionarily conserved function and regulation. Each individual scs gene shows a different role in copper and/or H2O2 resistance, indicating hierarchical contributions of these factors in the defense against these intoxicants. A protective effect of Cu preincubation against H2O2 toxicity and the increased Cu-mediated activation of cpxP in the ΔscsABCD mutant suggest that the CpxR/CpxA-controlled transcription of the ScsABCD system contributes to prevent Cu toxicity and to restore the redox balance at the Salmonella envelope.IMPORTANCE Copper intoxication triggers both specific and nonspecific responses in Salmonella The scs locus, which codes for periplasmic thiol/disulfide-oxidoreductase/isomerase-like proteins, has been the focus of attention because it is necessary for copper resistance, oxidative stress responses, and virulence and because it is not present in nonpathogenic Escherichia coli Still, the conditions under which the scs locus is expressed and the roles of its individual components remain unknown. In this report, we examine the contribution of each Scs factor to survival under H2O2 and copper stress. We establish that the scs genes form a copper-activated operon controlled by the CpxR/CpxA signal transduction system, and we provide evidence of its conserved gene arrangement and regulation in other bacterial pathogens.