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  • Review Article
  • Published:

Cyclic di-GMP: second messenger extraordinaire

Key Points

  • Cyclic di-GMP (c-di-GMP) is a global bacterial second messenger that controls a wide range of cellular processes that contribute to surface adaptation, biofilm formation, cell cycle progression and virulence.

  • Cellular levels of c-di-GMP are controlled by enzyme classes that have antagonistic activities, diguanylate cyclases that synthesize c-di-GMP and phosphodiesterases that degrade c-di-GMP.

  • c-di-GMP controls cellular processes at the transcriptional, translational and post-translational level, and through an increasing number of c-di-GMP-binding proteins and riboswitches.

  • The binding of c-di-GMP to specific proteins can influence their activity, stability, interaction with other proteins or their subcellular localization.

  • c-di-GMP and other bacterial cyclic dinucleotides (CDNs) stimulate the mammalian innate immune response by binding to the stimulator of interferon genes (STING) receptor, thereby converging with the cyclic GMP–AMP synthase (cGAS)–cyclic GMP–AMP (cGAMP) cytosolic DNA-surveillance pathway.

Abstract

Cyclic dinucleotides (CDNs) are highly versatile signalling molecules that control various important biological processes in bacteria. The best-studied example is cyclic di-GMP (c-di-GMP). Known since the late 1980s, it is now recognized as a near-ubiquitous second messenger that coordinates diverse aspects of bacterial growth and behaviour, including motility, virulence, biofilm formation and cell cycle progression. In this Review, we discuss important new insights that have been gained into the molecular principles of c-di-GMP synthesis and degradation, which are mediated by diguanylate cyclases and c-di-GMP-specific phosphodiesterases, respectively, and the cellular functions that are exerted by c-di-GMP-binding effectors and their diverse targets. Finally, we provide a short overview of the signalling versatility of other CDNs, including c-di-AMP and cGMP–AMP (cGAMP).

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Figure 1: Components of the c-di-GMP signalling network.
Figure 2: Role of c-di-GMP in C. crescentus pole morphogenesis and cell cycle progression.
Figure 3: Role of c-di-GMP in biofilm formation and dispersal.
Figure 4: Role of c-di-GMP in the virulence of Clostridium difficile.
Figure 5: General concepts of c-di-GMP signalling modules.

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Acknowledgements

The authors thank the reviewers for very constructive comments that have helped to improve both the accuracy and quality of this article. Work in the authors' laboratory was supported by the Swiss National Science Foundation (grant 310030B_147090 to U.J.) and by a European Research Council (ERC) Advanced Research Grant (322809 to U.J.).

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Glossary

GGDEF domains

Catalytic domains of diguanylate cyclases that are responsible for the condensation of two GTP molecules to cyclic di-GMP (c-di-GMP). The domain is named after its conserved signature motif Gly-Gly-Asp-Glu-Phe.

Receiver domain

A conserved amino-terminal domain of response regulators that receives a phosphoryl group from a histidine kinase to activate a carboxy-terminal output domain.

I site

An allosteric binding site for cyclic di-GMP (c-di-GMP) that is responsible for substrate inhibition of diguanylate cyclases.

EAL domain

A catalytic domain of phosphodiesterases that is responsible for the hydrolysis of cyclic di-GMP (c-di-GMP). The EAL domain is named after its conserved signature motif Glu-Ala-Leu and cleaves c-di-GMP into the linear molecule 5′-phosphoguanylyl-(3′-5′)-guanosine (pGpG).

HD-GYP domain

A catalytic domain of phosphodiesterases that is responsible for the cleavage of cyclic di-GMP (c-di-GMP) into two molecules of GMP. The domain belongs to a subclass of HD phosphohydrolases that contain an additional Gly-Tyr-Pro signature motif.

Riboswitches

Regulatory segments of an mRNA that can bind to a small molecule, which results in the altered stability or translation efficiency of the mRNA.

PilZ domain

A small prototypical cyclic di-GMP (c-di-GMP)-binding domain. PilZ domain-containing proteins represent the best-studied class of c-di-GMP effectors.

YajQ protein family

A family of poorly characterized bacterial proteins with motifs that are characteristic of nucleotide-binding or nucleic acid-binding proteins.

ATPases

Enzymes that catalyse the hydrolysis of ATP and harness the energy that is released to drive chemical reactions.

Mannose-sensitive haemagglutinin pili

(MSHA pili). Type IV pili with haemagglutinating activity that are inhibited by mannosides.

Sensor histidine kinases

Enzymes that autophosphorylate a conserved histidine residue and transfer this moiety to the receiver domain of a response regulator.

Birth scar protein

A protein that is positioned at the site of cytokinesis and acts as a marker for the newly formed poles of daughter cells after cell division.

Vegetative hyphae

Filamentous, fungal-like cellular structures in a medium or on a colony surface.

Adhesins

Surface components of bacterial cells that facilitate adherence to other cells or to surfaces.

Extracellular matrix

A self-produced and secreted polymeric matrix that consists of sugars, proteins and DNA, in which bacteria are embedded within a surface-grown biofilm.

σS

A sigma factor in gammaproteobacteria that is a central regulator of the general stress response and of gene expression in stationary phase.

Haemolytic uraemic syndrome

(HUS). A clinical syndrome that is characterized by the destruction of red blood cells and acute kidney failure, and is caused primarily by infection with Shiga toxin-producing Escherichia coli.

Shiga-toxin

A family of related toxins that are expressed and secreted by various enteric pathogens, and inhibit protein synthesis in eukaryotic target cells.

Stimulator of interferon genes

(STING). A receptor that has an important role in innate immunity by inducing the production of type I interferons.

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Jenal, U., Reinders, A. & Lori, C. Cyclic di-GMP: second messenger extraordinaire. Nat Rev Microbiol 15, 271–284 (2017). https://doi.org/10.1038/nrmicro.2016.190

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