A cyclic oligonucleotide signaling pathway in type III CRISPR-Cas systems

Bacterial defense amplification Prokaryotic type III CRISPR systems use the effector complex and additional proteins such as Csm6 to destroy both the genome and the transcripts of invaders. However, how the effector complex and Csm6 coordinate CRISPR activity remains a mystery. Kazlauskiene et al. found that a cyclic oligonucleotide–based signaling pathway can regulate the defense response (see the Perspective by Amitai and Sorek). Upon target recognition, the Cas10 subunit of the effector complex synthesizes cyclic oligoadenylates, which act as second messengers to initiate and amplify the nuclease activity of Csm6. Science, this issue p. 605; see also p. 550 Cyclic oligoadenylates are signaling molecules that regulate type III-A CRISPR systems to provide full antiviral immunity in bacteria. Type III CRISPR-Cas systems in prokaryotes provide immunity against invading nucleic acids through the coordinated degradation of transcriptionally active DNA and its transcripts by the Csm effector complex. The Cas10 subunit of the complex contains an HD nuclease domain that is responsible for DNA degradation and two Palm domains with elusive functions. In addition, Csm6, a ribonuclease that is not part of the complex, is also required to provide full immunity. We show here that target RNA binding by the Csm effector complex of Streptococcus thermophilus triggers Cas10 to synthesize cyclic oligoadenylates (cAn; n = 2 to 6) by means of the Palm domains. Acting as signaling molecules, cyclic oligoadenylates bind Csm6 to activate its nonspecific RNA degradation. This cyclic oligoadenylate–based signaling pathway coordinates different components of CRISPR-Cas to prevent phage infection and propagation.