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cGAS STING Signalling Pathway

The cytosolic DNA-sensing cGAS-STING pathway in innate immunity. Cyclic GMP-AMP synthase (cGAS) is a protein, which detects various cytosolic dsDNA, including viral DNA, damaged self-DNA released by dying cells, micronuclei, and mitochondrial origins. dsDNA activates cGAS via forming cGAS-dsDNA in 2:2 complexes. Mitochondrial damage and the release of mitochondrial DNA (mtDNA) in the cytosol also activates cGAS. The interactions of cGAS with DNA induce the formation of the liquid droplets through a phase transition, in which cGAS exerts its catalytic role to create the second messenger cGAMP that stimulates the stimulator of interferon genes (STING) at the endoplasmic reticulum (ER). STING then translocates from the ER to Golgi compartments and recruits kinases such as TANK-binding kinase 1 (TBK1) and IκB kinase (IKK), which in turn catalyzes the phosphorylation of IFN regulatory factor 3 (IRF3) and the nuclear factor-κB (NF-κB) inhibitor IκBα. Phosphorylated IRF3 translocates to the nucleus to activate transcription of genes encoding type I interferons and other inflammatory genes. IκBα phosphorylation accelerates nucleus translocation of NF-κB to promote transcription of target inflammatory cytokines, leading to activating inflammatory responses.STING is a receptor for cyclic di-nucleotides (CDNs) that resides in the endoplasmic reticulum (ER). When STING binds to CDNs, it moves from the ER to the Golgi. STING is an endoplasmic reticulum (ER) protein. After STING binding to cGAMP, STING exits the ER and translocates to the Golgi, where STING triggers the type I interferon- and proinflammatory responses through the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB)