Sci Signaling . . . The results of the Guo Fei team reveal important molecular mechanisms that regulate cGAS-induced DNA.

Cyclic gmp-amp (cgamp) synthase (CGAs) can recognize foreign DNA and RNA:DNA The heterozygous chain catalyzes the production of the second messenger cyclic gmp-amp (cgamp), which binds to and activates sting, and then recruits and activates tbk1-irf3, eventually leading to the production of interferon and immune factors [1, 2]。after the foreign DNA enters the cell, it will form a granular structure (FOCI) which collects CGAs in the cytoplasm. However, the composition of foci and its role in the physiological process of CGAs recognizing exogenous DNA induced interferon need further experimental exploration.on November 26, Guo Fei, Institute of pathogenic biology, Chinese Academy of Medical Sciences, published a paper entitled PKR dependent cytosolic CGAs foci are necessary for intracellular DNA sensing on science signaling. It was found that CGAs could interact with the important protein g3bp1 of stress granules, promote the binding of CGAs with DNA and induce interferon.protein molecule PKR, which plays an important role in RNA recognition, can also interact with CGAs, and this interaction is of great significance for CGAs and DNA to form g3bp1 related particles.this work for the first time explained the main components of granules formed by CGAs and exogenous DNA in the cytoplasm, and showed the importance of the formation of such granules for CGAs to recognize exogenous DNA induced interferon and provide a theoretical basis for regulating innate immunity.the researchers first found that CGAs interacted with a large number of RNA binding proteins by immunoprecipitation combined with mass spectrometry, and then confirmed the RNA dependent interaction between the important protein g3bp1 and CGAs.immunofluorescence assay also found that DNA, CGAs and g3bp1 had obvious co localization after exogenous DNA stimulation.interestingly, the interaction between CGAs and g3bp1 is greatly enhanced in the presence of exogenous DNA.studies have shown that environmental stress can cause the activation of eIF2 α upstream kinase, which leads to the inhibition of translation initiation, and the mRNA and protein molecules in translation are suspended to form stress granules (SG) [3].PKR, a double stranded RNA mediated kinase, is an important kinase for phosphorylation of eIF2 α [4].the authors found that CGAs interacted with PKR to induce the formation of stress granules by phosphorylating PKR and then eIF2 α.in order to explore the role of CGAs in the formation of stress granules, researchers knocked out CGAs in HeLa cells and observed the formation of stress granules induced by DNA. The results showed that the ability of DNA to induce stress granules basically disappeared after CGAs knockout, indicating that DNA induced the formation of stress granules in cells through CGAs.in order to detect the role of this stress granular structure in CGAs induced interferon formation, the researchers knocked out the endogenous g3bp1 and PKR of THP-1, and then detected the activation level of interferon pathway after stimulation with ISD (interferon stimulatory DNA) or heat inactivated vacciavirus (vacciavirus).the results showed that g3bp1 or PKR could significantly inhibit the production of interferon induced by exogenous DNA, indicating that g3bp1 and PKR play an important role in DNA recognition induced interferon.in conclusion, CGAs can bind an important protein molecule g3bp1 of stress granules. Under DNA stimulation, CGAs can form a granular structure containing mRNA, g3bp1 and PKR, which plays an important role in DNA induced interferon production.stress granules have been reported to contain a variety of RNA recognition receptors, which can be used as a platform for RNA recognition and play an important role in cell recognition of RNA induced interferon production [5,6].this study demonstrated that CGAs, an important DNA receptor, could also be located in stress granules, and it also played an important role in the induction of interferon by DNA recognition, suggesting that stress granules are an important platform for recognizing exogenous nucleic acids (DNA and RNA) to induce innate immunity.this study also shows that DNA induced innate immunity can be controlled by steric hindrance, which has important theoretical significance for preventing the body from recognizing abnormal DNA induced autoimmunity.after the article was published, it was also selected as a recommended article by "this week in science" of current "science" magazine.it is reported that Hu Siqi, associate researcher of the Institute of pathogenic biology, Chinese Academy of Medical Sciences, doctoral students Sun Hong and Yin Lijin are the co first authors of the paper.researcher Guo Fei, Institute of pathogenic biology, Chinese Academy of Medical Sciences, and Professor Liang Chen of McGill University in Canada are co authors. 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