Molecular Mechanisms of CBASS-Mediated Bacteriophage Defense

The cyclic oligonucleotide-based anti-phage signaling system (CBASS) is an innate immune mechanism in bacteria that mediates phage defense through programmed cell death. The CBASS system utilizes cyclic oligonucleotides (cOs) synthesized by cGAS/DncV-like nucleotidyltransferases (CD-NTase) to activate CD-NTase-associated proteins (Caps). This process elicits three cytocidal effects: DNA degradation, membrane disruption and NAD⁺ depletion. These effects collectively block phage replication and dissemination by causing infected cells to self-destruct. To achieve immune evasion from CBASS, phages have evolved anti-CBASS proteins that disrupt the binding of cOs to Caps effectors. This enables intracellular phage replication, assembly and propagation. This review systematically elucidates the multidimensional defense strategies of CBASS, with a focus on the molecular mechanisms underlying its anti-phage defensive functions. It provides novel insights into understanding the evolutionary dynamics of phage-host interactions.