A <i>Campylobacter jejuni</i> sensor phosphatase–driven two-component system integrates metabolic phosphodonors as cues in signal transduction

Canonical bacterial two-component signal transduction systems (TCSs) detect cues by sensors with opposing kinase and phosphatase activities to alter the level of phosphorylation of cognate response regulators to mediate responses. We previously identified the <i><i>Campylobacter jejuni</i></i> BumSR TCS as the founding member of a bacterial TCS family in which the sensor solely functions as a phosphatase. Sensing specific intestinal metabolites inhibits BumS dephosphorylation of phospho-BumR (P-BumR) to impact BumR as a transcriptional regulator of genes influencing host colonization. Since BumS lacks kinase activity, BumR must depend upon a noncognate phosphodonor in the bacterium to form P-BumR. Through a genetic screen and selection, physiological assays, and biochemical analysis, we identified acetyl phosphate (AcP) and carbamoyl phosphate (CP) as natural in vivo phosphodonors for BumR. In <i><i>C. jejuni</i></i>, AcP and CP are products of metabolic pathways fueled by amino acids favored by the bacterium as carbon sources for growth. Producing and utilizing AcP and CP as bona fide BumR phosphodonors allows BumSR to integrate different types of inputs for signal transduction. Microbiota-generated gut metabolites are cues for BumS to control its phosphatase activity for P-BumR and inform about the spatial location of <i><i>C. jejuni</i></i> in host intestines. In contrast, AcP and CP are cues for BumR that directly influence P-BumR levels and activity and inform about the richness of favored carbon sources in intestinal niches for optimal energy generation and metabolism. Our study reveals how a bacterial TCS strategically integrates information from multiple cues through both essential components for optimal signal transduction.