Antiviral signalling by a cyclic nucleotide activated CRISPR protease

Christophe Marcel Joseph Rouillon*, Niels Schneberger, Haotian Chi, Katja Blumenstock, Stefano Da Vela, Katrin Ackermann, Jonas Moecking, Martin F. Peter, Wolfgang Boenigk, Reinhard Seifert, Bela Ernest Bode, Jonathan L. Schmid-Burgk, Dmitri Svergun, Matthias Geyer, Malcolm White, Gregor Hageluken*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
17 Downloads (Pure)

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 RNA3,4,5. 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.
Original languageEnglish
Pages (from-to)168–174
JournalNature
Volume614
Early online date24 Nov 2022
DOIs
Publication statusPublished - 2 Feb 2023

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