Comparisons of cyclic nucleotide-based immune systems in prokaryotes. (A) Protein Data Bank (PDB) identifiers are shown alongside all structures. Type III CRISPR immunity comprises four key components; a detection and signaling platform, cyclic nucleotide signals, ancillary signal sensors fused to effectors, and mechanisms to eliminate the signal. The type III CRISPR complex detects viral mRNA, and the Cas10 nucleotidyl cyclase generates cyclic oligoadenylates (cOA; cAn, n = 3–6) containing 3′–5′ phosphodiester linkages. cOA allosterically stimulates downstream CRISPR ancillary effector proteins, typically by binding to a CRISPR-associated Rossmann fold (CARF) domain (colored in marine and light blue in protein dimers). Finally, ring nucleases eliminate cOA and deactivate CRISPR ancillary effectors, controlling the immune response. Some ring nucleases are CARF family proteins, whereas others have unique cOA sensing domains. Viruses encode variant ring nucleases (AcrIII-1), which rapidly degrade cOA and suppress the type III CRISPR immune response. In some bacteria, AcrIII-1 is found associated with type III CRISPR systems and has been termed Crn2 because it appears to be harnessed by bacteria to regulate CRISPR immunity. (B) The cyclic oligonucleotide-based antiphage signaling system (CBASS) resembles the type III CRISPR immune system in some respects. The cyclase (CdnE) is activated by unknown stimuli during phage infection, and different CdnE proteins synthesize different cyclic nucleotide molecules which activate downstream effector proteins. CBASS can synthesize cyclic nucleotides containing both 3′–5′ and 2′–5′ phosphodiester linkages, giving rise to an enormous repertoire of possible cyclic nucleotide signals. These signals are detected by distinct protein domains, including the SMODS associated and fused to various effectors sensor domain (SAVED), which is evolutionarily linked to the CARF domain. Although ring nucleases may degrade cA4, no prokaryotic enzymes have been identified that degrade any of the other cyclic nucleotide signals generated by CBASS. Some CBASS systems may function exclusively via abortive infection, whereas others may have novel regulatory mechanisms.
