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Prof. Xuemin Zhang and Prof. Tao Li revealed a crucial mechanism of cGAS activity regulated by acetylation

 

On March 7, 2019, Cell published a paper entitled “Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity” from the research group directed by Professors Xue-Min Zhang and Tao Li. This study revealed a crucial mechanism of cGAS activity regulated by acetylation, demonstrating a new function of aspirin to inhibit DNA-induced autoimmunity by acetylating cGAS.

Upon infection, pathogen DNA will be released into cytoplasm and is recognized by cGAS. The detection of DNA by cGAS elicits antiviral responses.The abnormal activation of cGAS, however, leads to several autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) and Aicardi–Goutières syndrome (AGS).

Using by Mass Spectrometry, the researchers identified multiple acetylation sites of cGAS, including K384, K394 and K414. They first mutated these sites to mimic the acetylated lysine residues, and found these mutations inhibited cGAS activity. Next, they utilized CRISPR-Cas9, in vitro purified acetylated cGAS proteins and in vitro cGAMP synthesis assay to further confirm the acetylation-mediated cGAS inhibition.

By analyzing the acetylation sites of cGAS, the researchers found that aspirin may acetylate cGAS. They verified the inhibition effect of aspirin on cGAS in both cells and mice. To detect whether aspirin could be used to treat DNA-induced autoimmune diseases, the researchers utilized AGS mouse model and examined the inhibitory effect of aspirin on the disease phenotypes. They treated AGS mice with aspirin and found that the level of cGAS acetylation in these mice was increased and the autoimmune responses were reduced. Moreover, aspirin treatment significantly promoted the survival of mice. Using cells from an AGS patient and his elder healthy brother, the researchers found that aspirin inhibited the excessive immune responses in the cells from the AGS patient.

By revealing the key mechanism that acetylation blocks cGAS, this study found that the century-old drug, aspirin, could inhibit cGAS through acetylation. This discovery provides a new strategy for the treatment of AGS and other cGAS-related diseases.

Links: https://www.sciencedirect.com/science/article/pii/S0092867419300492