Ring nucleases deactivate Type III CRISPR ribonucleases by degrading cyclic oligoadenylate

The CRISPR system provides adaptive immunity against mobile genetic elements in prokaryotes, utilising small CRISPR RNAs which direct effector complexes to degrade invading nucleic acids1–3. Type III effector complexes were recently demonstrated to synthesise a novel second messenger, cyclic oligoadenylate (cOA), on binding target RNA4,5. cOA in turn binds to and activates ribonucleases and other factors via a CARF (CRISPR associated Rossman Fold) domain, inducing an antiviral state in the cell that is important for immunity. The mechanism of the “off-switch” that resets the system is not understood. Here, we report the identification of the nuclease that degrades these cOA ring molecules. The “Ring nuclease” is itself a CARF family protein with a metal independent mechanism, which cleaves cA(4) rings to generate linear di-adenylate species and switches off the antiviral state. The identification of Ring nucleases adds an important insight to the CRISPR system.