Type III CRISPR–Cas systems produce cyclic oligoadenylate second messengers

Ole Niewoehner, Carmela Garcia-Doval, Jakob T. Rostøl, Christian Berk, Frank Schwede, Laurent Bigler, Jonathan Hall, Luciano A. Marraffini and Martin Jinek ()
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Ole Niewoehner: University of Zurich
Carmela Garcia-Doval: University of Zurich
Jakob T. Rostøl: Laboratory of Bacteriology, The Rockefeller University
Christian Berk: Institute for Pharmaceutical Sciences
Frank Schwede: BIOLOG Life Science Institute GmbH
Laurent Bigler: University of Zurich
Jonathan Hall: Institute for Pharmaceutical Sciences
Luciano A. Marraffini: Laboratory of Bacteriology, The Rockefeller University
Martin Jinek: University of Zurich

Nature, 2017, vol. 548, issue 7669, 543-548

Abstract: Abstract In many prokaryotes, type III clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated (Cas) systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone RNase that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the interference complex, its Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CRISPR-associated Rossmann fold (CARF) domain. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to an unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity.

Date: 2017
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DOI: 10.1038/nature23467

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