Stimulator of
interferon genes (
STING) functions in the cytosolic
DNA-sensing pathway of innate immunity in mammals. It is activated upon binding the cyclic dinucleotide 2'3'-cGAMP, a second messenger produced by the
enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS), which acts as the receptor for
DNA in this pathway, and triggers the expression of
interferons and other viral stress-induced genes. The ancient origin of
STING in the evolution of animals had been noted, but its primitive function was speculative. We review here recent advances in the remarkable history of cGAS-
STING signaling, which establish that cGAS is a member of the family of cGAS/DncV-like
nucleotidyltransferases (CD-NTases). In bacteria, CD-NTases synthesize a wide range of cyclic
oligonucleotide second messengers in response to bacteriophage
infections, which in turn activate a variety of effector
proteins to abort phage
infection. Among these effectors, some are related to
STING, revealing an ancestral function for the cGAS-
STING cassette in
antiviral host defense. Study of
STING signaling in invertebrate animals is consistent with an early acquisition in the history of metazoans of CD-NTase- and
STING-encoding genes to counter the universal threat of viruses. In particular,
STING-dependent immunity appears to play a previously unsuspected important role in some insects. These discoveries open up interesting perspectives for the use of model organisms to decipher emerging aspects of cGAS-
STING biology in mammals, such as the activation of
interferon-independent responses or the function and regulation of cGAS in the nucleus.