The cystosolic DNA sensor cGAS catalyzes production of the second messenger cGAMP. In the Journal of Immunology, a paper by Stetson and colleagues, and in the Proceedings of the National Academy of Sciences USA, a separate study by Chen and colleagues, show that cGAS can sense aberrantly accumulated self DNA and initiate autoinflammatory disease. Deficiency in cellular exonucleases or endonucleases leads to the accumulation of cytosolic DNA, which then triggers excessive type I interferon via DNA sensors and autoinflammatory disease. However, nuclease-deficient mice that also lack cGAS are 'rescued' from a rampant type I interferon signature and disease. Even haploinsufficiency in cGAS can partially protect mice from the absence of certain nucleases. cGAMP is sensed downstream by the adaptor STING, whose knockout is similarly protective. Mice deficient in both the nuclease TREX1 and STING still accumulate cGAMP, but this is not pathogenic. Thus, cGAS is important for the recognition of cytosolic DNA and in driving certain autoinflammatory diseases.
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07 January 2016
In the version of this Research Highlight initially published, only the work of Gao et al. (Proc. Natl. Acad. Sci. USA 112, 12903–12904 (2015)) was discussed. This has been revised to include discussion of another article with very similar data published a few weeks earlier, by Gray et al. (J. Immunol. 195, 1939–1943 (2015)). The error has been corrected in the HTML and PDF versions of the article.
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Fehervari, Z. cGAS ramps up autoinflammatory disease. Nat Immunol 16, 1113 (2015). https://doi.org/10.1038/ni.3302
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DOI: https://doi.org/10.1038/ni.3302
