Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity
Open accessAbstract
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.
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Some old drugs such as aspirin and antimalarials quinacrine and chloroquine inhibit cGAS, suggesting that downregulating this pathway might confer health benefits.
“Interestingly, some old drugs such as aspirin146 and antimalarials quinacrine and chloroquine147 inhibit cGAS, further suggesting that downregulating this pathway might confer health benefits.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [146]
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References 66 · Cited by 371
- Authors
- Dai, J., Huang, Y.-J., He, X., Zhao, M., Wang, X., Liu, Z.-S., Xue, W., Cai, H., Zhan, X.-Y., Huang, S.-Y., He, K., Wang, H., Wang, N., Sang, Z., Li, T., Han, Q.-Y., Mao, J., Diao, X., Song, N., Chen, Y., Li, W.-H., Man, J.-H., Li, A.-L., Zhou, T., Liu, Z.-G., Zhang, X.-M., & Li, T.
- Affiliations
- National Center of Biomedical Analysis (CN)
- National Institutes of Health (US)
- Army Medical University (CN)
- Jilin University (CN)
- Corresponding author
- Zhang, Xue-Min
- Li, Tao
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 176
- Issue
- 6
- Pages
- 1447-1460.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8274936
- OpenAlex
- W2916717448
- Cited by
- 371
- References
- 66
- Citations by year
- 2026: 56 · 2025: 53 · 2024: 54 · 2023: 54 · 2022: 51 · 2021: 44 · 2020: 35 · 2019: 23 · 2013: 1
- FWCI
- 15.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- The National Key Research and Development Program of China (2017YFC1601100, 2017YFA0505602)
- National Natural Science Foundation of China (81771708, 81872153, 31570837, 81472273)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- cGAS, acetylation, aspirin, self-DNA, autoimmunity, Aicardi-Goutières syndrome, cytosolic DNA sensing, lysine acetylation, protein deacetylation, innate immune activation
- MeSH terms
- THP-1 Cells, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Acetylation, Amino Acid Sequence, Animals, Aspirin, Autoimmune Diseases, Cell Line, Disease Models, Animal, DNA, Exodeoxyribonucleases, HeLa Cells, Humans, Mice, Inbred C57BL, Models, Molecular, Mutation, Nervous System Malformations, Nucleotidyltransferases, Autoimmunity, Self Tolerance, Autoimmune Diseases of the Nervous System, Mice, HEK293 Cells
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