Intracellular copper homeostasis in bacteria is maintained as the result of a complex ensemble of cellular processes that in Escherichia coli involve the coordinated action of two systems, cue and cus. In contrast, the pathogenic bacterium Salmonella harbours only the cue regulon, including copA, which is shown here to be transcriptionally controlled by CueR. Mutant strains in the CueR-regulated genes were constructed to characterize the response of Salmonella enterica serovar Typhimurium to high concentrations of extracellular copper under both aerobic and anaerobic conditions. Unlike its counterpart in E. coli, inactivation of cuiD displays the most severe phenotype and is also required for copper tolerance under anaerobic conditions. Deletion of copA has a mild effect in aerobiosis, but strongly impairs survival in the absence of oxygen. In a DcopA strain, a second Salmonella-specific P-type ATPase, GolT, can substitute the copper transporter, diminishing the effect of its deletion. The overall results highlight the importance of the cue system for controlling intracellular copper stress. The observed differences between Salmonella and E. coli in handling copper excess may contribute to our understanding of the distinct capability of these related pathogenic bacteria to survive outside the host
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