cGAMP-activated cGAS-STING signaling: its bacterial origins and evolutionary adaptation by metazoans


Review


doi: 10.1038/s41594-023-00933-9.


Online ahead of print.

Affiliations

Item in Clipboard

Review

Dinshaw J Patel et al.


Nat Struct Mol Biol.


.

Abstract

The metazoan cGAMP-activated cGAS-STING innate immunity pathway is triggered in response to genomic instability and DNA damage, thereby providing host defense against microbial pathogens. This pathway also impacts on autophagy, cellular senescence and antitumor immunity, while its overactivation triggers autoimmune and inflammatory diseases. Metazoan cGAS generates cGAMP containing distinct combinations of 3′-5′ and 2′-5′ linkages, which target the adaptor protein STING and activate the innate immune response through a signaling cascade leading to upregulation of cytokine and interferon production. This Review highlights a structure-based mechanistic perspective of recent advances in cGAMP-activated cGAS-STING innate immune signaling by focusing on the cGAS sensor, cGAMP second messenger and STING adaptor components, thereby elucidating the specificity, activation, regulation and signal transduction features of the pathway. In addition, the Review addresses progress towards identification of inhibitors and activators targeting cGAS and STING, as well as strategies developed by pathogens to evade cGAS-STING immunity. Most importantly, it highlights cyclic nucleotide second messengers as ancient signaling molecules that elicit a potent innate immune response that originated in bacteria and evolved through evolutionary adaptation to metazoans.

References

    1. Athukoralage, J. S. & White, M. F. Cyclic nucleotide signaling in phage defense and counter-defense. Annu. Rev. Virol. 9, 451–468 (2022).



      PubMed



      DOI

    1. Zaver, S. A. & Woodward, J. J. Cyclic dinucleotides at the forefront of innate immunity. Curr. Opin. Cell Biol. 63, 49–56 (2020).



      PubMed



      PMC



      DOI

    1. Patel, D. J., Yu, Y. & Jia, N. Bacterial origins of cyclic nucleotide-activated antiviral immune signaling. Mol. Cell 82, 4591–4610 (2022).



      PubMed



      DOI

    1. Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016).



      PubMed



      DOI

    1. Cai, X., Chiu, Y. H. & Chen, Z. J. The cGAS–cGAMP–STING pathway of cytosolic DNA sensing and signaling. Mol. Cell 54, 289–296 (2014).



      PubMed



      DOI

Read more here: Source link