CRISPR-Cas supervises diverse anti-phage defense systems

A variety of bacterial anti-phage systems have recently been discovered1-3, but how these systems synergize to defend against diverse phages remains poorly understood. Here, we report that the adaptive immune system CRISPR-Cas supervises the expression of diverse immune systems by exploiting the regulatory CRISPR RNA-like RNAs (crlRNAs). The crlRNAs target and inhibit the promoters of various immune systems, including the newly characterized Nezha and Gabija, as well as eight previously unrecognized systems that feature distinct defensive domains. Notably, CRISPR regulation balances the expression level of these systems to ensure effective anti-phage activity while avoiding their autoimmunity risks. In return, the supervised immune systems trigger abortive infections when CRISPR-Cas is inhibited by viral anti-CRISPR proteins, thereby offering an anti-anti-CRISPR protection at the population level. Moreover, these systems complement CRISPR immunity with a differing anti-phage profile. These findings highlight the pivotal role of CRISPR-Cas in orchestrating a diverse range of immune systems and showcase the delicate synergy among the multilayered defense strategies in prokaryotes.