Abstract
Two-component signaling systems (TCSs) are one of the mechanisms that bacteria employ to sense and adapt to changes in the environment. A prototypical TCS functions as a phosphorelay from a membrane-bound sensor histidine kinase (HK) to a cytoplasmic response regulator (RR) that controls target gene expression. Despite significant homology in the signaling domains of HKs and RRs, TCSs are thought to typically function as linear systems with little to no cross-talk between non-cognate HK-RR pairs. Here we have identified several cell envelope acting compounds that stimulate a previously uncharacterized Bacillus anthracis TCS. Furthermore, this TCS cross-signals with the heme sensing TCS HssRS; therefore, we have named it HssRS interfacing TCS (HitRS). HssRS reciprocates cross-talk to HitRS, suggesting a link between heme toxicity and cell envelope stress. The signaling between HssRS and HitRS occurs in the parental B. anthracis strain; therefore, we classify HssRS-HitRS interactions as cross-regulation. Cross-talk between HssRS and HitRS occurs at both HK-RR and post-RR signaling junctions. Finally, HitRS also regulates a previously unstudied ABC transporter implicating this transporter in the response to cell envelope stress. This chemical biology approach to probing TCS signaling provides a new model for understanding how bacterial signaling networks are integrated to enable adaptation to complex environments such as those encountered during colonization of the vertebrate host.
Highlights
One mechanism by which bacteria sense and adapt to their environment is through the use of two-component signaling systems (TCSs)
We have identified a new TCS (HitRS), which is activated by compounds that alter the integrity of the cell envelope, and interacts with HssRS to coordinate a simultaneous response to both heme and cell envelope stress
While all activation of Phrt by heme is lost in DhssRS, Phrt is strongly activated upon ‘205 exposure in the absence of the HssS histidine kinase (HK) and its cognate response regulator (RR) HssR (Figure 2A and 2B)
Summary
One mechanism by which bacteria sense and adapt to their environment is through the use of two-component signaling systems (TCSs). In the presence of a specific signal, the HK autophosphorylates at a conserved intracellular histidine residue and transfers the phosphate to an aspartate on the cognate RR. This phosphorylation event activates the RR, which binds to target promoter regions and subsequently regulates gene expression [1]. In this manner the classic bacterial TCS is thought to function in a linear fashion, in that each HK has a defined input that results in a specific output from the RR. An activating signal is required in order to observe cross-regulation, but not cross-talk
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