Bioinformatic analysis of type III CRISPR systems reveals key properties and new effector families
Abstract
Recognition of RNA from invading mobile genetic elements (MGE) prompts type III CRISPR systems to activate an HD nuclease domain and/or a nucleotide cyclase domain in the Cas10 subunit, eliciting an immune response. The cyclase domain can generate a range of nucleotide second messengers, which in turn activate a diverse family of ancillary effector proteins. These provide immunity by non-specific degradation of host and MGE nucleic acids or proteins, perturbation of membrane potentials, transcriptional responses, or the arrest of translation. The wide range of nucleotide activators and downstream effectors generates a complex picture that is gradually being resolved. Here, we carry out a global bioinformatic analysis of type III CRISPR loci in prokaryotic genomes, defining the relationships of Cas10 proteins and their ancillary effectors. Our study reveals that cyclic tetra-adenylate is by far the most common signalling molecule used and that many loci have multiple effectors. These typically share the same activator and may work synergistically to combat MGE. We propose four new candidate effector protein families and confirm experimentally that the Csm6-2 protein, a highly diverged, fused Csm6 effector, is a ribonuclease activated by cyclic hexa-adenylate.
Citation
Hoikkala , V P , Graham , S & White , M 2024 , ' Bioinformatic analysis of type III CRISPR systems reveals key properties and new effector families ' , Nucleic Acids Research , vol. 52 , no. 12 , pp. 7129–7141 . https://doi.org/10.1093/nar/gkae462
Publication
Nucleic Acids Research
Status
Peer reviewed
ISSN
0305-1048Type
Journal article
Description
Funding: European Research Council Advanced Grant [REF 101018608 to M.F.W.]; V.H. was funded by the Finnish Cultural Foundation. Funding for open access charge: University of St Andrews.Collections
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