2. Academic Validation
  3. Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity

Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity

  • Cell. 2019 Mar 7;176(6):1447-1460.e14. doi: 10.1016/j.cell.2019.01.016.
Jiang Dai 1,  Yi-Jiao Huang 2,  Xinhua He 3,  Ming Zhao 2,  Xinzheng Wang 2,  Zhao-Shan Liu 2,  Wen Xue 2,  Hong Cai 2,  Xiao-Yan Zhan 2,  Shao-Yi Huang 1,  Kun He 2,  Hongxia Wang 2,  Na Wang 2,  Zhihong Sang 2,  Tingting Li 2,  Qiu-Ying Han 2,  Jie Mao 2,  Xinwei Diao 4,  Nan Song 2,  Yuan Chen 2,  Wei-Hua Li 2,  Jiang-Hong Man 2,  Ai-Ling Li 2,  Tao Zhou 2,  Zheng-Gang Liu 5,  Xue-Min Zhang 6,  Tao Li 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
  • 2 State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
  • 3 State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China.
  • 4 State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; Department of Pathology, Xinqiao Hospital, 3(rd) Military Medical University, Chongqing 400037, China.
  • 5 Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 6 State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; Cancer Research Institute of Jilin University, the First Hospital of Jilin University, Changchun, Jilin Province 130021, China. Electronic address: zhangxuemin@cashq.ac.cn.
  • 7 State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China; State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis, 27 Tai-Ping Road, Beijing 100850, China. Electronic address: tli@ncba.ac.cn.
PMID: 30799039 DOI: 10.1016/j.cell.2019.01.016
Abstract

The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by Cyclic GMP-AMP Synthase (cGAS) to elicit Anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.

Keywords

Aicardi-Goutiéres syndrome; Trex1; acetylation; aspirin; autoimmune disease; cGAS; interferonopathies.

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