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NRI AT 20: INNATE IMMUNITY

A billion-year-old mechanism of innate immunity uncovered

Nature Reviews Immunology volume 21, page 620 (2021)Cite this article

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Viruses are the most abundant pathogens on earth. Every organism must defend itself against viral infection to survive. In humans and other vertebrates, the central mediators of antiviral immunity are type I interferons, secreted molecules that are produced by virally infected cells and act to inhibit viral replication and spread. Although the critical antiviral function of type I interferons was elucidated in the 1950s, the processes allowing cells to produce type I interferons after viral infection remained unclear for a long time. Until 2013, when a most fundamental antiviral signalling pathway, the cGAS–STING pathway, was discovered.

In one of two landmark studies, Zhijian (James) Chen and his team first revealed that the presence of DNA inside the cytosol elicits the production of a transferable immune-stimulatory molecule, which — surprisingly — was neither a protein nor a nucleic acid molecule (Wu et al., 2013). Instead, they showed that a cyclic dinucleotide, cyclic GMP–AMP (cGAMP), is produced in DNA-stimulated cells that, in turn, engages a sensor known as stimulator of interferon genes (STING) to mediate the induction of type I interferons. Further research then demonstrated that this endogenous cyclic dinucleotide bears a unique linkage chemistry rendering it exquisitely potent to activate human STING (Ablasser et al., 2013; Diner et al., 2013; Gao et al., 2013). In a second study, back-to-back to the first one, Chen and colleagues also purified and characterized the enzyme responsible for cGAMP catalysis, a member of the nucleotidyltransferase family, which they accordingly named cGAMP synthase (cGAS) (Sun et al., 2013).

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References

Original articles

  • Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013)

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Authors and Affiliations

  1. Global Health Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland

    Andrea Ablasser

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  1. Andrea Ablasser
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Correspondence to Andrea Ablasser.

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A.A. is a scientific co-founder of IFM Due.

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Ablasser, A. A billion-year-old mechanism of innate immunity uncovered. Nat Rev Immunol 21, 620 (2021). https://doi.org/10.1038/s41577-021-00613-z

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