Abstract
Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.
Key points
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Cyclic GMP–AMP synthase (cGAS) is an evolutionarily conserved cytosolic nucleic acid sensor that synthesizes the cyclic dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which engages stimulator of interferon genes (STING) to trigger the production of inflammatory cytokines, including type I interferons.
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Extracellular cGAMP is hydrolysed by transmembrane and soluble ectonucleotide pyrophosphatase/phosphodiesterase 1, and enters neighbouring cells via cGAMP importers. Transfer to adjoining and distant cells enables cGAMP to act as an immunotransmitter and modulate antiviral responses, antitumour immunity and tumour metastasis.
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Activation of cGAS–STING by genomic or mitochondrial self DNA has been implicated in numerous autoinflammatory, autoimmune and neurodegenerative diseases, cell senescence and ageing, as well as in acute and chronic kidney injury.
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The microbiome can stimulate or inhibit cGAS–STING via cGAS sensing of commensal DNA, microorganism-induced endogenous retroviruses, or self DNA released owing to infection-induced cell damage. These interactions can affect gut and skin homeostasis.
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Modulating the proteins involved in the activation of the cGAS–STING pathway and its regulators provides therapeutic opportunities to attenuate or enhance cGAS–STING-driven inflammatory responses.
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Acknowledgements
We thank Tomas Mustelin, Christian Lood and Grant Hughes for helpful discussions. This work was supported by the following grants: 1R21AR079661-01, DOD LR200061 and Hitchcock Foundation Scholar Award (to SSG) and R21AR077842 and the Alliance for Lupus Research (to K.B.E.).
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K.B.E. and J.A. are co-founders of Amdax Therapeutics, LLC. S.S.-G. declares no competing interests.
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Glossary
- Micronuclei
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Small membrane-bound compartments that contain genomic DNA and form during mitosis in certain pathological states.
- Retroelements
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Genetic elements that can be incorporated into a DNA sequence after reverse transcription of an RNA molecule.
- Necroptosis
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A form of regulated cell death involving the activation of receptor-interacting protein kinases-1 (RIPK1) and RIPK3, and cell rupture (that is, necrosis).
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Skopelja-Gardner, S., An, J. & Elkon, K.B. Role of the cGAS–STING pathway in systemic and organ-specific diseases. Nat Rev Nephrol 18, 558–572 (2022). https://doi.org/10.1038/s41581-022-00589-6
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DOI: https://doi.org/10.1038/s41581-022-00589-6