How the PhoP/PhoQ System Controls Virulence and Mg2+ Homeostasis: Lessons in Signal Transduction, Pathogenesis, Physiology, and Evolution

The PhoP/PhoQ two-component system governs virulence, Mg2+ homeostasis, and resistance to a variety of antimicrobial agents, including acidic pH and cationic antimicrobial peptides, in several Gram-negative bacterial species. Best understood in Salmonella enterica serovar Typhimurium, the PhoP/PhoQ system consists of the sensor PhoQ and the transcriptional regulator PhoP. PhoQ is activated by multiple signals, including low Mg2+, certain antimicrobial peptides, and long-chain unsaturated fatty acids via its periplasmic domain, a mildly acidic pH via its cytoplasmic domain, and an increase in osmolarity by its transmembrane domains. When activated, PhoQ promotes the phosphorylated state of PhoP. Phosphorylated PhoP (PhoP-P) binds to its target DNA sequences and modifies transcription of the corresponding genes. Some PhoP-regulated gene products alter PhoP-P amounts, even under constant inducing conditions. PhoP-P controls the abundance of hundreds of proteins both directly, by having transcriptional effects on the corresponding genes, and indirectly, by modifying the abundance, activity, or stability of other transcription factors, regulatory RNAs, protease regulators, and metabolites. The investigation of PhoP/PhoQ has uncovered novel forms of signal transduction and the physiological consequences of regulon evolution.