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Cyclic di-AMP: another second messenger enters the fray

Nature Reviews Microbiology volume 11, pages 513–524 (2013)Cite this article

Subjects

Key Points

  • When faced with stresses in a rapidly changing environment, bacteria must be able to sense these changes and coordinate responses rapidly. To do this, they use a number of nucleotide signalling molecules that act as second messengers to transduce signals around the cell.

  • Cyclic di-AMP (c-di-AMP) is a recently discovered signalling nucleotide that is present in many Gram-positive bacteria, a limited number of Gram-negative species and also probably in some archaea.

  • This signalling molecule is synthesized by cyclase enzymes, which condense two molecules of ATP to c-di-AMP using the enzymatic activity that is contained within the DisA_N domain, a domain that is distinct from other dinucleotide cyclase domains.

  • c-di-AMP is degraded to the linear molecule pApA by the action of phosphodiesterases containing a DHH–DHHA1 domain architecture.

  • Following synthesis, c-di-AMP binds to a specific set of receptor or target proteins and allosterically alters their function (or the function of downstream effector proteins). To date, five c-di-AMP receptors have been identified, namely c-di-AMP receptor regulator (DarR), which is involved in the regulation of fatty acid synthesis in Mycobacterium smegmatis; KtrA, cation proton antiporter A (CpaA) and KdpD, which are all potentially linked to potassium or ion transport in Staphylococcus aureus; and PstA, a protein of unknown function.

  • Although the exact pathways have yet to be fully worked out, a number of phenotypes associated with altered c-di-AMP levels in the cell have now been characterized. For instance, c-di-AMP is linked to the sensing of DNA integrity in Bacillus subtilis and to cell wall homeostasis in multiple species, and can also induce a eukaryotic immune response when secreted by the bacterium Listeria monocytogenes.

Abstract

Nucleotide signalling molecules contribute to the regulation of cellular pathways in all forms of life. In recent years, the discovery of new signalling molecules in bacteria and archaea, as well as the elucidation of the pathways they regulate, has brought insights into signalling mechanisms not only in bacterial and archaeal cells but also in eukaryotic host cells. Here, we provide an overview of the synthesis and regulation of cyclic di-AMP (c-di-AMP), one of the latest cyclic nucleotide second messengers to be discovered in bacteria. We also discuss the currently known receptor proteins and pathways that are directly or indirectly controlled by c-di-AMP, the domain structure of the enzymes involved in its production and degradation, and the recognition of c-di-AMP by the eukaryotic host.

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Figure 1: Cyclic di-AMP production.
Figure 2: Domain architecture of known and predicted bacterial cyclic di-AMP synthases and hydrolases.
Figure 3: Cyclic di-AMP receptor proteins.
Figure 4: The cyclic di-AMP signalling network.
Figure 5: Induction of a type I interferon response by bacteria.

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Acknowledgements

Work in the A.G. laboratory is currently supported by the European Research Council (grant 260371) and the Wellcome Trust (grant 100289).

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  1. Section of Microbiology and Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, London, SW7 2AZ, UK

    Rebecca M. Corrigan & Angelika Gründling

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  1. Rebecca M. Corrigan
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Correspondence to Angelika Gründling.

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Phylogenetic distribution of DAC and PDE enzymes (PDF 235 kb)

Glossary

Nucleotidyl transferase superfamily

A family of enzymes that transfer nucleotides onto phosphosugars.

Forespore

The smaller of the two compartments that are formed by asymmetrical division of the sporulating cell. The forespore matures into an endospore.

Phosphoenolpyruvate-dependent sugar phosphotransferase system EIIA

A subunit of the protein EII, an enzyme responsible for the import and phosphorylation of sugars that are imported through this major carbohydrate transport system in bacteria and archaea.

Tetratricopeptide repeat

A structural motif found in tandem arrays of 3–16 repeats. These motifs form scaffolds to promote protein–protein interactions.

PAS sensory domain

A domain that is named for its conservation in the proteins Per, ARNT and Sim and their homologues. The PAS domain binds a diverse range of small-molecule ligands (for example, haem and FAD) and is often involved in redox and light responses.

DHH domain

A domain that is found in a family of phosphatases and is characterized by the presence of a conserved DHH amino acid motif.

Surface plasmon resonance

A way of measuring the interaction of macromolecules at a surface through changes in the refractive index. Valence electrons of molecules at a metal–liquid interface oscillate in response to incident light. When one ligand is immobilized on a metal surface (for example, using a hexahistidine tag) and a second ligand is passed across the surface, the association and dissociation of the two ligands result in a change of refractive index, which can be measured.

Major facilitator family transporter

A family of transporters that are responsible for transporting small solutes across the membrane in response to chemiosmotic ion gradients.

Regulator of conductance of potassium family

A family of proteins that often function as ligand-gated potassium channels.

Lipoteichoic acid

A cell wall polymer that, in many cases, consists of a polyglycerolphosphate chain which is inserted into the bacterial membrane through a glycolipid anchor.

Type I interferon response

An immune response that is traditionally associated with viral infection, but is now known to also be important in the response to bacteria. It involves the secretion of cytokines, including interferon-α (IFNα) and IFNβ, by many mammalian cells.

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Corrigan, R., Gründling, A. Cyclic di-AMP: another second messenger enters the fray. Nat Rev Microbiol 11, 513–524 (2013). https://doi.org/10.1038/nrmicro3069

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