title: Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases.
abstract: TREX1 is an exonuclease that digests DNA in the cytoplasm. Loss-of-function mutations of TREX1 are linked to Aicardi-Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE) in humans. Trex1(-/-) mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of interferon (IFN)-induced genes (ISGs). Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates the IFN pathway. Upon binding to DNA, cGAS is activated to catalyze the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce IFNs and other cytokines. Here we show that genetic ablation of cGas in Trex1(-/-) mice eliminated all detectable pathological and molecular phenotypes, including ISG induction, autoantibody production, aberrant T-cell activation, and lethality. Even deletion of just one allele of cGas largely rescued the phenotypes of Trex1(-/-) mice. Similarly, deletion of cGas in mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescued the lethal autoimmune phenotypes of the DNaseII(-/-) mice. Through quantitative mass spectrometry, we found that cGAMP accumulated in mouse tissues deficient in Trex1 or DNaseII and that this accumulation was dependent on cGAS. These results demonstrate that cGAS activation causes the autoimmune diseases in Trex1(-/-) and DNaseII(-/-) mice and suggest that inhibition of cGAS may lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
authors.forename: Daxing
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
authors.forename: Tuo
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Animal Resource Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
authors.forename: Mary
authors.initials: M
authors.lastname: Wight-Carter
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148; Zhijian.Chen@UTSouthwestern.edu.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D000242:Cyclic AMP / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004789:Enzyme Activation; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D001323:Autoantibodies; D000242:Cyclic AMP; D016207:Cytokines; D004247:DNA; D005090:Exodeoxyribonucleases; D018836:Inflammation Mediators; D009713:Nucleotidyltransferases; D010750:Phosphoproteins; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C429526:three prime repair exonuclease 1
keywords: DNaseII; Trex1; autoimmune disease; cGAMP; cGAS