The BvgS PAS Domain, an Independent Sensory Perception Module in the Bordetella bronchiseptica BvgAS Phosphorelay

Abstract

To detect and respond to the diverse environments they encounter, bacteria often use two-component regulatory systems (TCS) to coordinate essential cellular processes required for survival. In pathogenic Bordetella species, the BvgAS TCS regulates expression of hundreds of genes, including those encoding all known protein virulence factors, and its kinase activity is essential for respiratory infection. Maintenance of BvgS kinase activity in the lower respiratory tract (LRT) depends on the function of another TCS, PlrSR. While the periplasmic Venus flytrap domains of BvgS have been implicated in responding to so-called modulating signals in vitro (nicotinic acid and MgSO4), a role for the cytoplasmic Per-Arnt-Sim (PAS) domain in signal perception has not previously been demonstrated. By comparing B. bronchiseptica strains with mutations in the PAS domain-encoding region of bvgS with wild-type bacteria in vitro and in vivo, we found that although the PAS domain is not required to sense modulating signals in vitro, it is required for the inactivation of BvgS that occurs in the absence of PlrS in the LRTs of mice, suggesting that the BvgS PAS domain functions as an independent signal perception domain. Our data also indicate that the BvgS PAS domain is important for controlling absolute levels of BvgS kinase activity and the efficiency of the response to modulating signals in vitro. Our results provide evidence that BvgS integrates sensory inputs from both the periplasm and the cytoplasm to control precise gene expression patterns under diverse environmental conditions. IMPORTANCE Despite high rates of vaccination, pertussis, a severe, highly contagious respiratory disease caused by the bacterium Bordetella pertussis, has reemerged as a significant health threat. In Bordetella pertussis and the closely related species Bordetella bronchiseptica, activity of the BvgAS two-component regulatory system is critical for colonization of the mammalian respiratory tract. We show here that the cytoplasmic PAS domain of BvgS can function as an independent signal perception domain that influences BvgS activity in response to environmental conditions. Our work is significant because it reveals a critical, yet previously unrecognized, role for the PAS domain in the BvgAS phosphorelay and provides a greater understanding of virulence regulation in Bordetella.

ChiS is a noncanonical DNA-binding hybrid sensor kinase that directly regulates the chitin utilization program in Vibrio cholerae

“…ChiS has a C-terminal PAS domain (SI Appendix, Fig. S10A), which may modulate ChiS enzymatic activities through small ligand binding or mediating protein-protein interactions as described for other HKs (29,30). The complex regulation of ChiS activity may serve to integrate additional cues that ultimately control expression of the chitin utilization program.…”

Structural Insight into the Role of the PAS Domain for Signal Transduction in Sensor Kinase BvgS

“…Thus, the reason for the presence of a PAS domain in BvgS might go beyond facilitating the shift between states of activity. Signal perception and mechanical transmission are not mutually exclusive, and several cytoplasmic PAS domains are involved in sensing, particularly energy pathways (42,43). We screened a library of small molecules using a thermal shift assay but could not identify bona fide ligands of the BvgS PAS domain (E. Lesne, personal communication).…”

Diversity in Sensing and Signaling of Bacterial Sensor Histidine Kinases

“…Dupré et al concluded that the major function of the PAS domain is to maintain the conformational tension imposed by the periplasmic moiety of BvgS [157]. A recent study suggested that the BvgS PAS domain may function as an independent signal perception domain, as shown by in vivo animal experiments using B. bronchiseptica strains with mutations in the PAS domain [158].…”