Cyclic oligoadenylate signaling and regulation by ring nucleases during type III CRISPR defense

Biomedical Sciences Research Complex, School of Biology, University of St. Andrews, KY16 9ST St. Andrews, United Kingdom

Corresponding author: jsa8{at}st-andrews.ac.uk

Abstract

In prokaryotes, CRISPR-Cas immune systems recognize and cleave foreign nucleic acids to defend against mobile genetic elements (MGEs). Type III CRISPR-Cas complexes also synthesize cyclic oligoadenylate (cOA) second messengers, which activate CRISPR ancillary proteins involved in antiviral defense. In particular, cOA-stimulated nucleases degrade RNA and DNA nonspecifically, which slows MGE replication but also impedes cell growth, necessitating mechanisms to eliminate cOA in order to facilitate cell recovery. Extant cOA is degraded by a new class of enzyme termed a “ring nuclease,” which cleaves cOA specifically and switches off CRISPR ancillary enzymes. Several ring nuclease families have been characterized to date, including a family used by MGEs to circumvent CRISPR immunity, and encompass diverse protein folds and distinct cOA cleavage mechanisms. In this review we examine cOA signaling, discuss how different ring nucleases regulate the cOA signaling pathway, and reflect on parallels between cyclic nucleotide-based immune systems to reveal new areas for exploration.

Keywords

Footnotes

Abbreviations: Acr, anti-CRISPR; Afu, Archaeoglobus fulgidus; A₄ > P, tetra-adenylate containing 5′-hydroxyl and 2′3′-cyclic phosphate; A₂P, di-adenylate containing 5′-hydroxyl and 3′-phosphoryl; cA_{3, 4 or 6}, cyclic tri-, tetra-, or hexa-adenylate; Can1, CRISPR ancillary nuclease 1; CARF, CRISPR-associated Rossmann fold; Cas, CRISPR-associated; CBASS, cyclic oligonucleotide-based antiphage signaling system; cGAS, cyclic GMP-AMP synthase; Cmr, Cas module RAMP; cOA, cyclic oligoadenylate; Csm, Cas subtype Mtube; Csx, CRISPR-associated of unknown function; CRISPR, clustered regularly interspaced short palindromic repeats; Crn1/2/3, CRISPR ring nuclease 1, 2, or 3; HEPN, higher eukaryotes and prokaryotes nucleotide binding; MAD, membrane-associated DHH-DHHA1; MGE, mobile genetic element; Mpi, Marinitoga piezophila; SAVED, SMODS-associated and fused to various effector domain; SIRV1/2, Sulfolobus islandicus rudivirus 1/2; Sso, Sulfolobus solfataricus; ssRNA, single-stranded RNA; STAS, sulfate transporter and anti-sigma factor antagonist; STING, stimulator of interferon genes; 3′3′-cGAMP, cyclic 3′5′-linked GMP-AMP; 2′3′-cGAMP, cyclic 2′5′-, and 3′5′-linked GMP-AMP
Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.078739.121.
Freely available online through the RNA Open Access option.

This article, published in RNA, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.