Temporal and evolutionary dynamics of two-component signaling pathways

Abstract

Bacteria sense and respond to numerous environmental signals through two-component signaling pathways. Typically, a given stimulus will activate a sensor histidine kinase to autophosphorylate and then phosphotransfer to a cognate response regulator, which can mount an appropriate response. Although these signaling pathways often appear to be simple switches, they can also orchestrate surprisingly sophisticated and complex responses. These temporal dynamics arise from several key regulatory features, including the bifunctionality of histidine kinases as well as positive and negative feedback loops. Two-component signaling pathways are also dynamic on evolutionary time-scales, expanding dramatically in many species through gene duplication and divergence. Here, we review recent work probing the temporal and evolutionary dynamics of two-component signaling systems.

Figure 1. Temporal dynamics of two-component systems

(A) PhoQ-PhoP is a canonical two-component system that is activated by low extracellular Mg⁺⁺, changes in pH, and certain antimicrobial peptides. Upon sensing a stimulus, PhoQ is predominantly in the kinase state, driving PhoP phosphorylation and the increased expression of PhoP target genes, including phoPQ and mgrB (left). As MgrB accumulates, it helps drive a switch of PhoQ from the kinase to the phosphatase state. Eventually PhoQ is predominantly a phosphatase, limiting expression of PhoP-dependent genes (right). (B) This negative feedback loop mediated by MgrB likely accounts for the partial adaptation in pathway output. (C) Sporulation in B. subtilis is initiated by a four step phosphorelay. KinA (shown) or KinB/C/D/E first autophosphorylate; a phosphoryl group is then transferred to the response regulator Spo0F, then to the histidine phosphotransferase Spo0B, and finally to Spo0A (black arrows). Phosphorylated Spo0A directly promotes expression of itself and Spo0F (solid grey arrows), and indirectly promotes the production of KinA (dashed grey arrow). Phosphorylated Spo0A also indirectly drives dephosphorylation of itself and Spo0F (dashed grey lines). (D) Somehow these feedback loops produce pulses of phosphorylated Spo0A in sporulation-inducing conditions. Each pulse exhibits higher levels until a threshold level is reached to initiate sporulation.

Figure 2. Evolution of two-component systems

(a) Canonical two-component systems expand and diversify through gene duplication and subsequent divergence. After a pathway duplication, the specificity residues on the two identical systems diverge, such that each pathway continues to interact while reducing cross-talk between the two systems. (b) Two possible model for the origin of the phosphorelay driving B. subtilis sporulation. (top) Two canonical two-component pathways could have merged, with the response regulator of one pathway becoming the phosphodonor to another histidine kinase which then lost autophosphorylation activity. (bottom) KinA could have evolved to cross-talk with an existing response regulator with subsequent co-option of Spo0B as a histidine phosphotransferase and changes in KinA to prefer Spo0F over Spo0A.