Activation of master virulence regulator PhoP in acidic pH requires the Salmonella-specific protein UgtL

Acidic conditions, such as those inside phagosomes, stimulate the intracellular pathogen Salmonella enterica to activate virulence genes. The sensor PhoQ responds to a mildly acidic pH by phosphorylating, and thereby activating, the virulence regulator PhoP. This PhoP/PhoQ two-component system is conserved in a subset of Gram-negative bacteria. PhoQ is thought to be sufficient to activate PhoP in mildly acidic pH. However, we found that the Salmonella-specific protein UgtL, which was horizontally acquired by Salmonella before the divergence of S. enterica and Salmonella bongori, was also necessary for PhoQ to activate PhoP under mildly acidic pH conditions but not for PhoQ to activate PhoP in response to low Mg²⁺ or the antimicrobial peptide C18G. UgtL increased the abundance of phosphorylated PhoP by stimulating autophosphorylation of PhoQ, thereby increasing the amount of the phosphodonor for PhoP. Deletion of ugtL attenuated Salmonella virulence and further reduced PhoP activation in a strain bearing a form of PhoQ that is not responsive to acidic pH. These data suggest that when Salmonella experiences mildly acidic pH, PhoP activation requires PhoQ to detect pH and UgtL to amplify the PhoQ response. Our findings reveal how acquisition of a foreign gene can strengthen signal responsiveness in an ancestral regulatory system.