Journal Article

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

Gao, Daxing, Li, Xiao-Dong, Li, Quan-Zhen, Wight-Carter, Mary, Chen, Zhijian J., Li, Tuo, Chen, Xiang

2015

Overview

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 ofcGasinTrex1−/− 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 ofcGaslargely rescued the phenotypes ofTrex1−/− mice. Similarly, deletion ofcGasin mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescued the lethal autoimmune phenotypes of theDNaseII−/− 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 inTrex1−/− andDNaseII−/− mice and suggest that inhibition of cGASmay lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Autoantibodies - biosynthesis / Autoimmune diseases / Autoimmune Diseases - enzymology / Autoimmune Diseases - genetics / Autoimmune Diseases - immunology / Binding sites / Biological Sciences / Cyclic AMP - biosynthesis / Cytokines - metabolism / Cytoplasm / Deoxyribonucleic acid / DNA / DNA - metabolism / Enzyme Activation / Exodeoxyribonucleases - genetics / Exodeoxyribonucleases - metabolism / Inflammation Mediators - metabolism / Lymphocyte Activation / Mass spectrometry / Mice / Mice, Knockout / Nucleotidyltransferases - genetics / Nucleotidyltransferases - metabolism / Phosphoproteins - genetics / Phosphoproteins - metabolism / PNAS Plus / Rodents / T-Lymphocytes - immunology