Abstract
TREX1 is an exonuclease that digests DNA in the cytoplasm. Lossof-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 cGASmay lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.
| Original language | English (US) |
|---|---|
| Pages (from-to) | E5699-E5705 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 112 |
| Issue number | 42 |
| DOIs | |
| State | Published - Oct 20 2015 |
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Keywords
- Autoimmune disease
- CGAMP
- CGAS
- DNaseII
- Trex1
ASJC Scopus subject areas
- General
Cite this
Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. / Gao, Daxing; Li, Tuo; Li, Xiao Dong; Chen, Xiang; Li, Quan Zhen; Wight-Carter, Mary; Chen, Zhijian J.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 42, 20.10.2015, p. E5699-E5705.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases
AU - Gao, Daxing
AU - Li, Tuo
AU - Li, Xiao Dong
AU - Chen, Xiang
AU - Li, Quan Zhen
AU - Wight-Carter, Mary
AU - Chen, Zhijian J.
PY - 2015/10/20
Y1 - 2015/10/20
N2 - TREX1 is an exonuclease that digests DNA in the cytoplasm. Lossof-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 cGASmay lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.
AB - TREX1 is an exonuclease that digests DNA in the cytoplasm. Lossof-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 cGASmay lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.
KW - Autoimmune disease
KW - CGAMP
KW - CGAS
KW - DNaseII
KW - Trex1
UR - http://www.scopus.com/inward/record.url?scp=84947245185&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947245185&partnerID=8YFLogxK
U2 - 10.1073/pnas.1516465112
DO - 10.1073/pnas.1516465112
M3 - Article
C2 - 26371324
AN - SCOPUS:84947245185
VL - 112
SP - E5699-E5705
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 42
ER -