Reciprocal growth control by competitive binding of nucleotide second messengers to a metabolic switch in Caulobacter crescentus

Crosstalk between small-molecule regulated networks controls growth in Caulobacter crescentus. Bacteria use small signalling molecules such as (p)ppGpp or c-di-GMP to tune their physiology in response to environmental changes. It remains unclear whether these regulatory networks operate independently or whether they interact to optimize bacterial growth and survival. We report that (p)ppGpp and c-di-GMP reciprocally regulate the growth of Caulobacter crescentus by converging on a single small-molecule-binding protein, SmbA. While c-di-GMP binding inhibits SmbA, (p)ppGpp competes for the same binding site to sustain SmbA activity. We demonstrate that (p)ppGpp specifically promotes Caulobacter growth on glucose, whereas c-di-GMP inhibits glucose consumption. We find that SmbA contributes to this metabolic switch and promotes growth on glucose by quenching the associated redox stress. The identification of an effector protein that acts as a central regulatory hub for two global second messengers opens up future studies on specific crosstalk between small-molecule-based regulatory networks.

Automated summary

This study demonstrates that the small signaling molecules (p)ppGpp and c-di-GMP reciprocally regulate the growth of Caulobacter crescentus by converging on the small-molecule-binding protein SmbA. (p)ppGpp promotes growth on glucose, while c-di-GMP inhibits glucose consumption, with SmbA playing a role in this metabolic switch and quenching redox stress associated with growth on glucose. The identification of SmbA as a central regulatory hub for these two global second messengers suggests potential for future studies on specific crosstalk between small-molecule-based regulatory networks.