Fig. 3. Mechanisms of activation of the cGAS–STING pathway.

In the cytoplasm, cyclic GMP–AMP synthase (cGAS) can be activated by microbial or host DNA. The best-studied sources of cGAS-activating nucleic acids are DNA viruses and host mitochondria. However, several other DNA sources and cGAS-activating stimuli, such as endogenous retroelement DNA, micronuclei generated in senescent cells or owing to genomic instability, and the formation of chromatin bridges, have been reported^40,41,44,195. Microbe-induced cell fusion also enables the release of chromatin into the cytosol and RNA viruses can promote cGAS activation through ribosomal collision^79,81. Finally, certain DNA-binding proteins such as polyglutamine-binding protein 1 (PQBP1) might co-activate cGAS in combination with the HIV capsid protein⁷⁷ or Tau¹³⁸.