Cyclic oligoadenylate signaling and regulation by ring nucleases during type III CRISPR defense

In prokaryotes, CRISPR-Cas immune systems recognize and cleave foreign nucleic acids to defend against mobile genetic elements (MGEs). Type III CRISPR-Cas complexes also synthesize cyclic oligoadenylate (cOA) second messengers, which activate CRISPR ancillary proteins involved in antiviral defense. In particular, cOA-stimulated nucleases degrade RNA and DNA nonspecifically, which slows MGE replication but also impedes cell growth, necessitating mechanisms to eliminate cOA in order to facilitate cell recovery. Extant cOA is degraded by a new class of enzyme termed a "ring nuclease," which cleaves cOA specifically and switches off CRISPR ancillary enzymes. Several ring nuclease families have been characterized to date, including a family used by MGEs to circumvent CRISPR immunity, and encompass diverse protein folds and distinct cOA cleavage mechanisms. In this review we examine cOA signaling, discuss how different ring nucleases regulate the cOA signaling pathway, and reflect on parallels between cyclic nucleotide-based immune systems to reveal new areas for exploration.