Antiviral signalling by a cyclic nucleotide activated CRISPR protease

Christophe Rouillon (), Niels Schneberger, Haotian Chi, Katja Blumenstock, Stefano Vela, Katrin Ackermann, Jonas Moecking, Martin F. Peter, Wolfgang Boenigk, Reinhard Seifert, Bela E. Bode, Jonathan L. Schmid-Burgk, Dmitri Svergun, Matthias Geyer, Malcolm F. White and Gregor Hagelueken ()
Additional contact information
Christophe Rouillon: University of Bonn
Niels Schneberger: University of Bonn
Haotian Chi: University of St Andrews
Katja Blumenstock: University of Bonn and University Hospital Bonn
Stefano Vela: European Molecular Biology Laboratory (EMBL), Hamburg Site
Katrin Ackermann: University of St Andrews, North Haugh
Jonas Moecking: University of Bonn
Martin F. Peter: University of Bonn
Wolfgang Boenigk: Max Planck Institute for Neurobiology of Behavior—caesar
Reinhard Seifert: Max Planck Institute for Neurobiology of Behavior—caesar
Bela E. Bode: University of St Andrews, North Haugh
Jonathan L. Schmid-Burgk: University of Bonn and University Hospital Bonn
Dmitri Svergun: European Molecular Biology Laboratory (EMBL), Hamburg Site
Matthias Geyer: University of Bonn
Malcolm F. White: University of St Andrews
Gregor Hagelueken: University of Bonn

Nature, 2023, vol. 614, issue 7946, 168-174

Abstract: Abstract CRISPR defence systems such as the well-known DNA-targeting Cas9 and the RNA-targeting type III systems are widespread in prokaryotes1,2. The latter orchestrates a complex antiviral response that is initiated through the synthesis of cyclic oligoadenylates after recognition of foreign RNA3–5. Among the large set of proteins that are linked to type III systems and predicted to bind cyclic oligoadenylates6,7, a CRISPR-associated Lon protease (CalpL) stood out to us. CalpL contains a sensor domain of the SAVED family7 fused to a Lon protease effector domain. However, the mode of action of this effector is unknown. Here we report the structure and function of CalpL and show that this soluble protein forms a stable tripartite complex with two other proteins, CalpT and CalpS, that are encoded on the same operon. After activation by cyclic tetra-adenylate (cA4), CalpL oligomerizes and specifically cleaves the MazF homologue CalpT, which releases the extracytoplasmic function σ factor CalpS from the complex. Our data provide a direct connection between CRISPR-based detection of foreign nucleic acids and transcriptional regulation. Furthermore, the presence of a SAVED domain that binds cyclic tetra-adenylate in a CRISPR effector reveals a link to the cyclic-oligonucleotide-based antiphage signalling system.

Date: 2023
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DOI: 10.1038/s41586-022-05571-7

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