Turned On by a Low pH

Science's STKE  01 May 2007:
Vol. 2007, Issue 384, pp. tw147
DOI: 10.1126/stke.3842007tw147

Salmonellae, facultative intracellular pathogens that cause gastroenteritis and typhoid fever, respond to the normally inhospitable environment inside macrophage phagosomes--in which pathogens are exposed to antimicrobial peptides, reactive oxygen species, and acidic pH--by activating the transcription of virulence genes. This process, which depends on phagosomal acidification, involves the activation of the membrane-bound sensor kinase PhoQ, which leads to its autophosphorylation and the subsequent phosphorylation of the transcriptional activator PhoP (the PhoPQ system). Using a bacterial strain that expressed a reporter that was transcriptionally activated by PhoP, Prost et al. showed that, in the presence of 1 mM Mg2+ (the estimated phagosomal concentration), transcription increased when the pH was decreased from 7.5 to 5.5. When PhoQ was reconstituted in vesicles so that the periplasmic sensor domain faced inward and the cytoplasmic kinase domain faced outward, PhoP phosphorylation increased when lumenal pH was decreased from 7.5 to 5.5. Subinhibitory concentrations of antimicrobial peptides have previously been shown to activate PhoQ through a mechanism that may involve displacement of divalent cations, and the effects of antimicrobial peptides and pH on PhoP phosphorylation and PhoPQ-dependent transcription were additive. Nuclear magnetic resonance (NMR) spectroscopy revealed that the conformation of the PhoQ sensor domain was affected by changes in pH and that this conformational change did not depend on loss of divalent cation binding. Thus, the authors propose that PhoQ acts as a pH sensor and that antimicrobial peptides and low pH work together in macrophage phagosomes to activate the PhoPQ system.

L. R. Prost, M. E. Daley, V. Le Sage, M. W. Bader, H. Le Moual, R. E. Klevit, S. I. Miller, Activation of the bacterial sensor kinase PhoQ by acidic pH. Mol. Cell 26, 165-174 (2007). [Online Journal]