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Versatile modes of cellular regulation via cyclic dinucleotides

Nature Chemical Biology volume 13, pages 350–359 (2017)Cite this article

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Abstract

Since the discovery of c-di-GMP almost three decades ago, cyclic dinucleotides (CDNs) have emerged as widely used signaling molecules in most kingdoms of life. The family of second messengers now includes c-di-AMP and distinct versions of mixed cyclic GMP-AMP (cGAMP) compounds. In addition to these nucleotides, a vast number of proteins for the production and turnover of these molecules have been described, as well as effectors that translate the signals into physiological responses. The latter include, but are not limited to, mechanisms for adaptation and survival in prokaryotes, persistence and virulence of bacterial pathogens, and immune responses to viral and bacterial invasion in eukaryotes. In this review, we will focus on recent discoveries and emerging themes that illustrate the ubiquity and versatility of cyclic dinucleotide function at the transcriptional and post-translational levels and, in particular, on insights gained through mechanistic structure-function analyses.

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Figure 1: CDN signaling.
Figure 2: Bacterial CDNs and representative regulatory mechanisms.
Figure 3: Conformational adaptability and mechanism of action of CDNs.
Figure 4: Tripartite transmembrane signaling through HAMP-domaincontaining proteins with active or degenerate GGDEF and EAL domains.
Figure 5: Structures and nucleotide recognition of c-di-GMP-regulated transcription factors.
Figure 6: CDN-dependent regulation of ion transport.
Figure 7: c-di-GMP-dependent regulation of exopolysaccharide secretion in biofilms.
Figure 8: CDN recognition by STING.

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Acknowledgements

We thank F. Yildiz for critically reading a draft of the review, and N. Reyes, R. Fronzes and R. Cooley for useful discussions. Work in the Sondermann laboratory is supported by US National Institutes of Health grant R01-AI097307 (H.S.). P.V.K. is supported by the Centre National de la Recherche Scientifique (CNRS) and the Institute for Integrative Biology of the Cell (I2BC) and was previously a recipient of a Roux-Cantarini postdoctoral fellowship from the Institut Pasteur.

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Authors and Affiliations

  1. Unité G5 Biologie Structurale de la Sécrétion Bactérienne, UMR 3528 – CNRS, Institut Pasteur, Paris, France

    Petya Violinova Krasteva

  2. Structural Biology of Biofilms Group, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris Sud, Gif sur Yvette, France

    Petya Violinova Krasteva

  3. Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA

    Holger Sondermann

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  1. Petya Violinova Krasteva
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  2. Holger Sondermann
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Correspondence to Petya Violinova Krasteva or Holger Sondermann.

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Krasteva, P., Sondermann, H. Versatile modes of cellular regulation via cyclic dinucleotides. Nat Chem Biol 13, 350–359 (2017). https://doi.org/10.1038/nchembio.2337

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