Transporters as information processors in bacterial signalling pathways

Abstract

Summary Transporters are essential players in bacterial growth and survival, since they are key for uptake of nutrients on the one hand, and for defence against endogenous and environmental stresses on the other hand. Remarkably, in addition to their primary role in substrate translocation, it has become clear that some transporters have acquired a secondary function as sensors and information processors in signalling pathways. In this review, we describe recent advances in our understanding of the role of transporters in such signalling cascades, and discuss some of the emergent dynamic behaviour found in hallmark examples. A particular focus is placed on new insights into mechanistic details of information transfer between transporters and regulatory proteins. Quantitative considerations reveal that these signalling complexes can implement a remarkable diversity of regulatory logic functions, where the transporter can act as activity switch, as positive or negative reporter of transport flux, or as a signalling hub for the integration of multiple inputs. Such a dual use of transport proteins not only enables efficient substrate translocation but is also an elegant strategy to integrate important information about the cell's external conditions with its current physiological state.

The UzcRS two‐component system in Caulobacter crescentus integrates regulatory input from diverse auxiliary regulators

“…The coupling of transporter activity with stimulus perception by a TCS is commonly mediated via complex formation between the transporter and the HK (Piepenbreier et al ., ). To test whether UrtAP interacts with UzcRS, a co‐immunoprecipitation (Co‐IP) assay was performed in a strain containing C‐terminal HA‐tagged UrtP (UrtP‐HA) and N‐terminal 3× FLAG‐tagged UzcS expressed from their respective chromosomal loci.…”

“…While many HK that employ co‐sensing strategies (e.g. PhoBR and BceAB (Piepenbreier et al ., )) lack prototypical periplasmic sensing domains (i.e. are intramembrane sensing HKs (Mascher et al ., )) relying instead on the accessory regulator for signal perception, UzcS contains a predicted ~124 AA periplasmic domain where signal perception likely occurs (Fig.…”

“…Transporters are well suited as accessory regulators given their membrane localization and ability to selectivity bind and translocate substrates (e.g. nutrients, toxins) across the membrane (Tetsch and Jung, ; Piepenbreier et al ., ). As such, transporters can affect HK activity indirectly by altering the concentration of the signaling substrate and/or directly through a protein‐protein interaction with the HK that affects the phosphotransfer process (Witan et al ., ; Dintner et al ., ; Unden et al ., ).…”

“…This includes mechanisms for (i) the combinatorial integration of distinct signaling inputs (Cangelosi et al ., ; Unden et al ., ), (ii) establishing regulatory connections between seemingly independent regulatory pathways (Kato and Groisman, ; Eguchi et al ., ; Gerken et al ., ), (iii) altering the sensitivity of the HK for its cognate inducers (Cangelosi et al ., ), (iv) directly sensing nutrient scavenging or detoxification functions (e.g. flux sensing (Fritz et al ., ; Piepenbreier et al ., )) and (v) fine‐tuning response dynamics of the TCS (e.g. positive and negative feedback loops [Kato et al ., ; Salazar et al ., ]).…”

“…This sense‐and‐respond function is commonly mediated by two‐component systems (TCS) that are comprised of a membrane‐bound sensor histidine kinase (HK) that perceives the environmental cue and a cytosolic response regulator (RR) that is regulated through reversible phosphorylation by the HK and carries out the gene regulatory function of the TCS (Hoch and Silhavy, ; Krämer and Jung, ). While this two‐component paradigm is sufficient to mediate a response to certain environmental cues, a growing body of evidence supports the involvement of auxiliary regulators in the signal perception and transduction process of TCS (Mitrophanov and Groisman, , Tetsch and Jung, ; Buelow and Raivio, ; Krämer and Jung, ; Gebhard, ; Piepenbreier et al ., ).…”