Bacterial cGAS senses a viral RNA to initiate immunity

CBASS immunity protects prokaryotes from viral (phage) attack through the production of cyclic oligonucleotides, which activate effector proteins that trigger the death of the infected host. How bacterial cyclases recognize phage infection is unknown. Here, we show that staphylococcal phages produce a structured RNA transcribed from the terminase subunit genes, termed CBASS-activating bacteriophage RNA (cabRNA), which binds to a positively charged surface on CdnE cyclases and promotes the synthesis of the cyclic dinucleotide cGAMP to activate the CBASS immune response. Phages that escape the CBASS defense harbor mutations that lead to the generation of a longer form of the cabRNA that cannot activate CdnE. Since the mammalian cyclase OAS also binds viral dsRNA during the interferon response, our results reveal a conserved mechanism for the activation of innate antiviral defense pathways.