The PhoP-PhoQ two-component regulatory system is a key player in the adaptation of several gram-negative bacteria to Mg2+-limiting environments and the mediation of virulence. The system consists of the inner membrane sensor PhoQ and the cytoplasmic regulator PhoP, encoded by the phoP locus. PhoP-PhoQ responds to extracellular Mg2+ and Ca2+ levels, with Mg2+ serving as the primary signal. The system controls the expression of numerous genes, including those involved in Mg2+ transport, lipopolysaccharide (LPS) modification, and resistance to antimicrobial peptides. In Salmonella, PhoP-PhoQ regulates at least 40 proteins, many of which are specific to the species and contribute to virulence. The system also interacts with other regulatory systems, such as the PmrA-PmrB system, to integrate multiple signals and coordinate cellular responses. The PhoP-PhoQ system is essential for the survival and virulence of Salmonella in host cells, and its dysfunction leads to attenuation of virulence. Additionally, PhoP-PhoQ plays a role in the virulence of other gram-negative pathogens, including Shigella flexneri and Yersinia pestis. The system's ability to respond to environmental cues and its extensive regulatory network make it a critical factor in the adaptation and survival of these bacteria.The PhoP-PhoQ two-component regulatory system is a key player in the adaptation of several gram-negative bacteria to Mg2+-limiting environments and the mediation of virulence. The system consists of the inner membrane sensor PhoQ and the cytoplasmic regulator PhoP, encoded by the phoP locus. PhoP-PhoQ responds to extracellular Mg2+ and Ca2+ levels, with Mg2+ serving as the primary signal. The system controls the expression of numerous genes, including those involved in Mg2+ transport, lipopolysaccharide (LPS) modification, and resistance to antimicrobial peptides. In Salmonella, PhoP-PhoQ regulates at least 40 proteins, many of which are specific to the species and contribute to virulence. The system also interacts with other regulatory systems, such as the PmrA-PmrB system, to integrate multiple signals and coordinate cellular responses. The PhoP-PhoQ system is essential for the survival and virulence of Salmonella in host cells, and its dysfunction leads to attenuation of virulence. Additionally, PhoP-PhoQ plays a role in the virulence of other gram-negative pathogens, including Shigella flexneri and Yersinia pestis. The system's ability to respond to environmental cues and its extensive regulatory network make it a critical factor in the adaptation and survival of these bacteria.