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

Abstract

The ability to respond to changes in pH is critical for all organisms. In Salmonella enterica, 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 has been 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 S. 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. Thus, 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.

PagR mediates the precise regulation of Salmonella pathogenicity island 2 gene expression in response to magnesium and phosphate signals in Salmonella Typhimurium

“…whereas acidic pH activation of PhoP and downstream subset PhoPactivated genes require the Salmonella-specific protein UgtL (Choi & Groisman, 2017). Our data confirmed that the activation of pagR by PhoP/Q in response to low Mg 2+ requires mgtA.…”

“…vated by different signals(Groisman & Mouslim, 2006;Park & Groisman, 2014). For example, low Mg 2+ activation of PhoP and over half of the downstream PhoP-activated genes require the Mg 2+ transporter MgtA(Park & Groisman, 2014), whereas acidic pH activation of PhoP and downstream subset PhoPactivated genes require the Salmonella-specific protein UgtL(Choi & Groisman, 2017). For example, low Mg 2+ activation of PhoP and over half of the downstream PhoP-activated genes require the Mg 2+ transporter MgtA(Park & Groisman, 2014), whereas acidic pH activation of PhoP and downstream subset PhoPactivated genes require the Salmonella-specific protein UgtL(Choi & Groisman, 2017).…”

A Family of Small Intrinsically Disordered Proteins Involved in Flagellum-Dependent Motility in Salmonella enterica

“…PhoP is a response regulator, forming a two-component regulatory system with its cognate sensor kinase, PhoQ. The active form of phosphorylated PhoP (PhoPϳP) controls the expression of target genes (55,56), including those encoded on Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2). In general, the expression of SPI-1 is negatively (57) and that of SPI-2 genes is positively controlled by PhoPϳP (58).…”

Gene expression kinetics governs stimulus-specific decoration of the Salmonella outer membrane

“…1B) (17, 29, 30). However, these sensors differ in that PmrB responds to a mildly acidic pH through protonation of periplasmic histidine residues (17), whereas PhoQ does so through its cytoplasmic region via a mechanism that does not involve histidine residues (31).…”

“…However, these sensors differ in that PmrB responds to a mildly acidic pH through protonation of periplasmic histidine residues (17), whereas PhoQ does so through its cytoplasmic region via a mechanism that does not involve histidine residues (31). In addition, full activation of the PhoP/PhoQ system under mildly acidic pH requires the PhoP-activated gene ugtL , which encodes a protein that stimulates PhoQ autophosphorylation (30). …”