STING is known to serve as a sensor of intracellular infection, based on its recognition of bacterial cyclic dinucleotides (CDNs), including cyclic diguanylate monophosphate (c-di-GMP) and cyclic diadenylate monophosphate (c-di-AMP). These molecules are bacterial second messengers and are produced by enzymes present in most bacterial genomes. CDNs activate STING signaling by changing the conformation of the STING homodimer. This homodimer recruits and activates TBK1, which in turn phosphorylates and activates IRF3, leading to type I interferon production (Fig. 3.22), similar to signaling by TLR-3 and MAVS (see Figs. 3.16 and 3.21). TRIF (downstream of TLR3), MAVS, and STING each contain a similar amino acid sequence motif at their carboxy termini that becomes serine-phosphorylated when these molecules are activated. It appears that this motif, when phosphorylated, recruits both TBK1 and IRF3, allowing IRF3 to be efficiently phosphorylated and activated by TBK1.
STING also plays a role in viral infections, since mice lacking STING are susceptible to infection by herpesvirus. But until recently, it was unclear whether
STING activates the kinase TBK1 to phosphorylate IRF3, which enters the nucleus and induces expression of type I interferon genes
First panel: cGAS resides in the cytoplasm and serves as a sensor of double-stranded DNA (dsDNA) from viruses. When cGAS binds dsDNA, its enzymatic activity is stimulated, leading to production of cyclic-GMP-AMP (cGAMP). Bacteria that infect cells produce second messengers such as cyclic dinucleotides, including cyclic diguanylate monophosphate (c-di-GMP) and cyclic diadenylate monophosphate (c-di-AMP). Second panel: cGAMP and other bacterial dinucleotides can bind and activate the STING dimer present on the ER membrane. Third panel: in this state STING activates TBK1, although the details of this interaction are still unclear. Active TBK1 activates IRF3, as described in Fig. 3.16.
STING recognized viral DNA directly or acted only downstream of an unknown viral DNA sensor. It was found that the introduction of DNA into cells, even without live infection, generated another second messenger molecule that activated STING. This second messenger was identified as cyclic guano-sine monophosphate-adenosine monophosphate (cyclic GMP-AMP), or cGAMP. cGAMP, like bacterial CDNs, binds both subunits of the STING dimer and activates STING signaling. This result also suggested the presence of a DNA sensor acting upstream of STING. Purification of the enzyme that produces cGAMP in response to cytosolic DNA identified a previously unknown enzyme, which was named cGAS, for cyclic GAMP synthase. cGAS contains a protein motif present in the nucleotidyltransferase (NTase) family of enzymes, which includes adenylate cyclase (the enzyme that generates the second messenger molecule cyclic AMP) and various DNA polymerases. cGAS can bind directly to cytosolic DNA, and this stimulates its enzymatic activity to produce cGAMP from GTP and ATP in the cytoplasm, activating STING. Mice harboring an inactivated cGAS gene show increased susceptibility to herpesvirus infection, demonstrating its importance in immunity.