Activation and self-inactivation mechanisms of the cyclic oligoadenylate-dependent CRISPR ribonuclease Csm6

Carmela Garcia-Doval, Frank Schwede, Christian Berk, Jakob T. Rostøl, Ole Niewoehner, Oliver Tejero, Jonathan Hall, Luciano A. Marraffini and Martin Jinek ()
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Carmela Garcia-Doval: University of Zurich
Frank Schwede: Biolog Life Science Institute GmbH & Co. KG
Christian Berk: ETH Zurich
Jakob T. Rostøl: The Rockefeller University
Ole Niewoehner: University of Zurich
Oliver Tejero: University of Zurich
Jonathan Hall: ETH Zurich
Luciano A. Marraffini: The Rockefeller University
Martin Jinek: University of Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Bacterial and archaeal CRISPR-Cas systems provide RNA-guided immunity against genetic invaders such as bacteriophages and plasmids. Upon target RNA recognition, type III CRISPR-Cas systems produce cyclic-oligoadenylate second messengers that activate downstream effectors, including Csm6 ribonucleases, via their CARF domains. Here, we show that Enteroccocus italicus Csm6 (EiCsm6) degrades its cognate cyclic hexa-AMP (cA6) activator, and report the crystal structure of EiCsm6 bound to a cA6 mimic. Our structural, biochemical, and in vivo functional assays reveal how cA6 recognition by the CARF domain activates the Csm6 HEPN domains for collateral RNA degradation, and how CARF domain-mediated cA6 cleavage provides an intrinsic off-switch to limit Csm6 activity in the absence of ring nucleases. These mechanisms facilitate rapid invader clearance and ensure termination of CRISPR interference to limit self-toxicity.

Date: 2020
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DOI: 10.1038/s41467-020-15334-5

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