DancE: A DNA-Activated Bacterial cGAS-like Enzyme in Antiphage Immune Defense

Vertebrate cGAS senses DNA and synthesizes cyclic GMP-AMP to launch an immune response through the adaptor protein STING. Bacterial cyclic oligonucleotide-based signaling systems (CBASS) are evolutionarily related to the metazoan cGAS-STING pathway, but the molecular cues triggering bacterial cGAS activation remain poorly understood. Here, we identify a cGAS-like enzyme, termed DancE (DNA-activated di-nucleotide cyclase in Escherichia), that is activated by binding to double-stranded DNA. DancE is repressed by the bacterial chaperone DnaK, which prevents DNA binding by DancE. We further identified lambda phage prohead protease gpC that activates DancE through its protease activity. These results provide an example of a bacterial cGAS-like enzyme that is activated by DNA but through a guard-like mechanism that normally suppresses DNA sensing, suggesting that DNA sensing by cGAS family proteins is an ancient antiviral strategy conserved across kingdoms of life.