An intracellular phosphorus-starvation signal activates the PhoB/PhoR two-component system in Salmonella enterica

Bacteria acquire P primarily as inorganic orthophosphate (Pi, PO₄^3-). Once internalized, Pi is rapidly assimilated into biomass during the synthesis of ATP. Because Pi is essential, but excessive ATP is toxic, the acquisition of environmental Pi is tightly regulated. In the bacterium Salmonella enterica (Salmonella), growth in Pi-limiting environments activates the membrane sensor histidine kinase PhoR, leading to the phosphorylation of its cognate transcriptional regulator PhoB and subsequent transcription of genes involved in adaptations to low Pi. Pi limitation promotes PhoR kinase activity by altering the conformation of a membrane signaling complex comprised of PhoR, the multicomponent Pi transporter system PstSACB and the regulatory protein PhoU. However, the identity of the Pi-starvation signal and how it controls PhoR activity remain unknown. Here, we identify conditions where the PhoB and PhoR signal transduction proteins can be maintained in an inactive state when Salmonella is grown in media lacking Pi. Our results demonstrate that PhoB/PhoR is activated by an intracellular P-insufficiency signal.