cGAS,核小体 z-bo 2020-10-30 425

　　In all mammals, cyclic GMP-AMP synthase (cGAS) can sense the invasion of pathogen DNA and stimulate inflammation signals, autophagy and apoptosis. cGAS works by detecting DNA in the wrong location. Under normal circumstances, DNA is tightly packed and protected in the nucleus. There is no reason for DNA to move freely in cells. When DNA fragments finally escape the nucleus and enter the cytoplasm, they usually show ominous signs, such as cell damage or foreign DNA from viruses or bacteria that have invaded the cell.

　　CGAS protein works by recognizing DNA in the wrong position. Under normal circumstances, it is dormant in the cell. However, when cGAS detects the presence of extranuclear DNA, it suddenly works. It produces another chemical substance 2'3'A, the second messenger called cyclic GMP-AMP (cGAMP) triggers a molecular chain reaction, the result of which reminds us of the abnormal presence of DNA in cells. .. At the end of this signal cascade, if the battery is repaired or damaged and cannot be repaired, the battery itself will be destroyed. However, the health and integrity of cells depend on the ability of cGAS to distinguish harmless DNA from foreign and autologous DNA released during cell damage and stress.

　　cGAS, as a DNA sensor protein, can trigger a natural immune response after microbial infection, cell stress and cancer. When activated by double-stranded DNA, cytoplasmic cGAS produces cGAMP, which triggers the production of inflammatory cytokines and type I interferon (IFN). CGAS also exists in the nucleus filled with genomic DNA, and chromatin is involved in limiting its enzymatic activity. However, the structural basis of cGAS chromatin suppression remains unclear.

　　In a new study, researchers at the Swiss Federal Institute of Technology in Lausanne and the University of Basel have determined the structure of 3.1 Angstrom cryo-EM (cryo-EM) used in combination with human cGAS and nucleosomes. .. The related findings were published online in the journal Nature on September 10, 2020, with the title "Structural Mechanism of Nucleosomes Inhibiting CGAS". CGAS has extensive contact with histone H2A-H2B heterodimers and acid spots of nucleosomal DNA. Structural and complementary biochemical analysis also showed that cGAS binds to the second nucleosome in trans. From a mechanical point of view, nucleosome binding anchors cGAS in a monomeric state. In this state, spatial damage will inhibit the false activation of cGAS by genomic DNA. These researchers found that the mutation at the cGAS-acid pocket interface is sufficient to eliminate the inhibitory effect of nucleosomes on cGAS in vitro and induce the enzymatic activity of cGAS on the genomic DNA of living cells. I find. This study revealed the structural basis of the interaction between cGAS and chromatin and identified a convincing mechanism that enables cGAS to self-non-self-identify genomic DNA.