Copper homeostasis networks in the bacterium Pseudomonas aeruginosa [Gene Regulation]

Bacterial copper (Cu+) homeostasis enables both precise metallation of diverse cuproproteins and control of variable metal levels. To this end, protein networks mobilize Cu+ to cellular targets with remarkable specificity. However, the understanding of these processes is rather fragmented. Here, we use genome-wide transcriptomic analysis by RNA-Seq to characterize the response of Pseudomonas aeruginosa to external 0.5 mM CuSO4, a condition that did not generate pleiotropic effects. Pre-steady (5 min) and steady state (2 h) Cu+ fluxes, resulted in distinct transcriptome landscapes. Cells quickly responded to Cu2+ stress by slowing down metabolism. This was restored once steady state was reached. Specific Cu+ homeostasis genes were strongly regulated in both conditions. Our systemwide analysis revealed induction of three Cu+ efflux systems (a P1B-ATPase, a porin and a resistance-nodulation-division (RND) system), and of a putative Cu+ binding periplasmic chaperone and the unusual presence of two cytoplasmic CopZ proteins. Both CopZ chaperones could bind Cu+ with high affinity. Importantly, novel transmembrane transporters likely mediating Cu+ influx were among those largely repressed upon Cu+ stress. Compartmental Cu+ levels appear independently controlled; the cytoplasmic Cu+ sensor CueR controls cytoplasmic chaperones and plasma membrane transporters; while CopR/S responds to periplasmic Cu+. Analysis of ΔcopR and ΔcueR mutant strains revealed a CopR regulon composed of genes involved in periplasmic Cu+ homeostasis and its putative DNA recognition sequence. In conclusion our study established a system-wide model of a network of sensors/regulators, soluble chaperones, and influx/efflux transporters that control theCu+ levels in P. aeruginosa compartments.

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