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Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):E5699-705. doi: 10.1073/pnas.1516465112. Epub 2015 Sep 14.

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

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
2
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;
3
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148;
4
Animal Resource Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
5
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.

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.

KEYWORDS:

DNaseII; Trex1; autoimmune disease; cGAMP; cGAS

Comment in

PMID:
26371324
PMCID:
PMC4620884
DOI:
10.1073/pnas.1516465112
[Indexed for MEDLINE]
Free PMC Article

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