Antiviral signalling by a cyclic nucleotide activated CRISPR protease
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.
Citation
Rouillon , C M J , Schneberger , N , Chi , H , Blumenstock , K , Da Vela , S , Ackermann , K , Moecking , J , Peter , M F , Boenigk , W , Seifert , R , Bode , B E , Schmid-Burgk , J L , Svergun , D , Geyer , M , White , M & Hageluken , G 2023 , ' Antiviral signalling by a cyclic nucleotide activated CRISPR protease ' , Nature , vol. 614 , pp. 168–174 . https://doi.org/10.1038/s41586-022-05571-7
Publication
Nature
Status
Peer reviewed
ISSN
0028-0836Type
Journal article
Description
Funding information: M.G. and J.L.S.B. are funded by the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy–EXC2151–390873048. M.F.W. acknowledges a European Research Council Advanced Grant (grant number 101018608) and the China Scholarship Council (REF: 202008420207 to H.C.). G.H. is grateful for funding by the Deutsche Forschungsgemeinschaft (grant number HA6805/6-1).Collections
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