A CARF domain-containing protein, Cam1, is shown to mediate membrane depolarization and growth arrest in response to type III CRISPR–Cas immunity. Structural and biochemical analyses reveal that the CARF domains of a Cam1 dimer bind cyclic tetra-adenylate second messengers. In vivo, Cam1 localizes to the membrane, is predicted to form a tetrameric transmembrane pore, and provides defense against viral infection through the induction of membrane depolarization and growth arrest. These results indicate that CRISPR immunity can operate through mechanisms beyond nucleic acid degradation, such as membrane depolarization and growth arrest. Cam1 is predicted to form a tetrameric pore, and its function is dependent on the binding of cyclic oligoadenylate molecules. Mutagenesis studies show that specific residues are essential for Cam1 function. Cam1 causes membrane depolarization, which leads to growth arrest without cell lysis. Cam1 homologues also mediate growth arrest and are involved in type III CRISPR–Cas immunity. Cam1 prevents phage replication by inducing membrane depolarization and growth arrest. The findings suggest that Cam1 plays an essential role in type III-A CRISPR–Cas immunity, particularly when the phage is recognized late in the infection cycle. The study highlights the evolutionary flexibility of type III CRISPR–Cas systems, which have co-opted effectors with activities beyond nucleic acid degradation to mediate an abortive infection mechanism that protects the host when the cell-autonomous CRISPR response is not available.A CARF domain-containing protein, Cam1, is shown to mediate membrane depolarization and growth arrest in response to type III CRISPR–Cas immunity. Structural and biochemical analyses reveal that the CARF domains of a Cam1 dimer bind cyclic tetra-adenylate second messengers. In vivo, Cam1 localizes to the membrane, is predicted to form a tetrameric transmembrane pore, and provides defense against viral infection through the induction of membrane depolarization and growth arrest. These results indicate that CRISPR immunity can operate through mechanisms beyond nucleic acid degradation, such as membrane depolarization and growth arrest. Cam1 is predicted to form a tetrameric pore, and its function is dependent on the binding of cyclic oligoadenylate molecules. Mutagenesis studies show that specific residues are essential for Cam1 function. Cam1 causes membrane depolarization, which leads to growth arrest without cell lysis. Cam1 homologues also mediate growth arrest and are involved in type III CRISPR–Cas immunity. Cam1 prevents phage replication by inducing membrane depolarization and growth arrest. The findings suggest that Cam1 plays an essential role in type III-A CRISPR–Cas immunity, particularly when the phage is recognized late in the infection cycle. The study highlights the evolutionary flexibility of type III CRISPR–Cas systems, which have co-opted effectors with activities beyond nucleic acid degradation to mediate an abortive infection mechanism that protects the host when the cell-autonomous CRISPR response is not available.