Recently, Li Tao’s research group and Zhang Xuemin’s research group from the Academy of Military Medical Sciences of the Academy of Military Sciences discovered a new regulator of cGAS, G3BP1, and found that a natural small molecule compound from green tea, EGCG, can inhibit cGAS activation. The study was published online Dec. 3 in Nature Immunology.
cGAS is a nucleotransferase that functions as a DNA sensor in mammals and is essential for host resistance to viral infection. cGAS can recognize cytoplasmic DNA and generate cGAMP, activate interferon-stimulating protein, regulate the secretion of downstream type I interferon and other cytokines, and initiate the body’s immune response. In recent years, relevant studies have shown that in addition to sensing virus invasion, abnormal activation of cGAS directly leads to the occurrence of a class of autoimmune diseases, such as systemic lupus erythematosus and AGS syndrome.
“The abnormal activation of cGAS is the direct cause of the pathogenesis of many important diseases, and many large international pharmaceutical groups and research teams are trying their best to find cGAS inhibitors.” Corresponding author of the paper, Dr. Li Tao of the Academy of Military Medical Sciences told “Science China Journal” Reporter, the team decided to start with the study of the regulatory mechanism of cGAS, and to find the regulatory targets that control the activation of cGAS, in order to provide new directions for the treatment of antiviral infections and related diseases.
The researchers first used mass spectrometry to identify an important regulator of cGAS, G3BP1, and further verified that this regulator plays a key role in cGAS-mediated immune responses through techniques such as gene editing. In-depth mechanism studies revealed that G3BP1 ensures that cGAS can efficiently recognize viral DNA by helping cGAS to form polymers.
More importantly, through the above regulatory mechanism study, the researchers further discovered that a natural small molecule compound from green tea, EGCG, can effectively inhibit cGAS activation. In addition, the researchers also used autoimmune animal models and cells from AGS patients to verify the effectiveness of EGCG in inhibiting cGAS in vivo.
This study not only revealed a key molecular mechanism of the body’s anti-viral infection, but also took the lead in reporting the first cGAS inhibitor in the world, providing a therapeutic strategy choice for a series of autoimmune diseases for which there is currently no treatment. Important breakthroughs in the frontiers of immunology.