Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases

By Daxing Gao, Tuo Li, Xiao-Dong Li, Xiang Chen, Quanzhen Li, M. Wight-Carter, Zhijian J. Chen. Proceedings of the National Academy of Sciences of the United States of America, 2015

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The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, background): “In tissues from trex1−/− mice, elevated cGAMP was detected by mass spectrometry; cGAMP detection in these mice was also dependent on wild-type cGAS, directly demonstrating that cGAS is activated in trex1−/− mice (Gao et al., 2015).”
cGAS is essential for cellular senescence (2017, result): “This conclusion is consistent with the previous reports that cGAS is activated by dsDNA independently of the DNA sequence and that cGAS activation by endogenous DNA causes autoimmune diseases in mice lacking the DNase Trex1 or DNaseII (22, 43, 44).”
Mitochondrial DNA in inflammation and immunity (2020, positive): “For example, TREX1, a DNA exonuclease, is frequently mutated in human patients with AGS and systemic lupus erythematosus (SLE) [89 – 91], and co-deletion of cGAS, STING, Interferon-a / b receptor (IFNAR) or IRF3 rescues this phenotype [92 – 98].”
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence (2017, positive): “Genetic defects that compromise endogenous DNA metabolism or instances that trigger massive, synchronized accumulation of dead cells represent examples of this phenomenon 26 27 28, 29 30.”