Bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) is a ubiquitous bacterial second-messenger molecule that is involved in the molecular decision between planktonic motile and sedentary bacterial 'lifestyles': that is, 'to swim or to stick'. In general, high c-di-GMP levels reduce the expression and/or activity of flagella and stimulate the expression of various adhesins and biofilm-associated exopolysaccharides (EPSs). In addition, c-di-GMP controls virulence of animal and plant pathogens and is involved in cell cycle control in certain bacteria.
c-di-GMP is synthesized by diguanylate cyclases (DGCs) and degraded by c-di-GMP phosphodiesterases (PDEs). DGC activity is provided by GGDEF domains and PDE activity is provided by either EAL or HD-GYP domains: the amino acid motifs after which they were named contribute to their respective enzymatic activities. Environmental and cellular signals control the expression and, through amino-terminal sensory domains, activities of DGCs and PDEs.
c-di-GMP functions by binding to, and allosterically affecting the activity of, effector components, which not only include different types of proteins, but also RNA that acts as a riboswitch.
c-di-GMP-binding effectors directly control diverse target processes, including transcription (if the effector is a transcription factor), transcriptional elongation or translation (if the effector is a riboswitch), regulated proteolysis and the activities of enzymes or complex cellular structures (for example, flagella or specific EPS synthesis and excretion machineries).
The multiplicity of DGCs, PDEs and c-di-GMP-binding effectors in many bacterial species allows a plethora of signals to be integrated. It also provides the basis for functional and spatial sequestration of some c-di-GMP control modules in separate pathways that can operate in parallel. Local operation requires direct macromolecular interactions between the 'cognate' DGCs, PDEs, effectors and targets that make up a specific c-di-GMP control module, and can involve dynamic localization to specific sites in the cell (for example, distinct cell poles).
Direct interactions between the components of specific c-di-GMP control modules seem to have allowed the evolution of systems with 'degenerate' GGDEF and EAL domain proteins that have 'given up' c-di-GMP metabolism, and rely on protein–protein interactions only. Nonetheless, these systems seem to remain 'evolutionarily trapped' in their old physiological context: that is, the control of motility and/or biofilm-related functions.
On the stage of bacterial signal transduction and regulation, bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) has long played the part of Sleeping Beauty. c-di-GMP was first described in 1987, but only recently was it recognized that the enzymes that 'make and break' it are not only ubiquitous in the bacterial world, but are found in many species in huge numbers. As a key player in the decision between the motile planktonic and sedentary biofilm-associated bacterial 'lifestyles', c-di-GMP binds to an unprecedented range of effector components and controls diverse targets, including transcription, the activities of enzymes and larger cellular structures. This Review focuses on emerging principles of c-di-GMP signalling using selected systems in different bacteria as examples.
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The author thanks U. Jenal for providing the figure in BOX 2 and for helpful discussions, and C. Pesavento for providing input on the manuscript. Work from the author's laboratory cited in this review has been supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and the Dr Hans Messner Stiftung.
The author declares no competing financial interests.
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Hengge, R. Principles of c-di-GMP signalling in bacteria. Nat Rev Microbiol 7, 263–273 (2009). https://doi.org/10.1038/nrmicro2109
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