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Although metal ions are well-known regulators of cGAS-STING activation, their impact on CBASS-mediated antiviral function remains largely unexplored. Here, we show that manganese (Mn\n                      <jats:sup>2+<\/jats:sup>\n                      ) serves as a key cofactor to enhance CBASS activation. Upon phage infection, the intracellular Mn\n                      <jats:sup>2+<\/jats:sup>\n                      level is elevated, and the gene expression of the Mn\n                      <jats:sup>2+<\/jats:sup>\n                      transportation system is upregulated. We found that Mn\n                      <jats:sup>2+<\/jats:sup>\n                      directly augments the activity of DncV, markedly boosting 3\u20323\u2032-cGAMP production. Consequently, the phospholipase CapV is activated more rapidly, driving premature bacterial cell lysis and curtailing phage replication. Notably, Mn\n                      <jats:sup>2+<\/jats:sup>\n                      also alleviates folate-mediated inhibition of DncV, underscoring its role as a potent modulator of cyclic dinucleotide signaling. Our findings reveal a mechanism through which Mn\n                      <jats:sup>2+<\/jats:sup>\n                      confers bacterial resistance to phages, mirroring the Mn\n                      <jats:sup>2+<\/jats:sup>\n                      -enhanced antiviral responses of mammalian cGAS-STING.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Bacteriophages pose a persistent threat to bacterial survival, driving the evolution of diverse antiviral systems, including the cyclic-oligonucleotide-based antiphage signaling system (CBASS) immunity. Here, we reveal that manganese (Mn\n                      <jats:sup>2+<\/jats:sup>\n                      ) acts as a pivotal cofactor for CBASS, directly enhancing the activity of the cGAS-like cyclase DncV to generate 3\u20323\u2032-cGAMP, which, in turn, activates the phospholipase CapV. This Mn\n                      <jats:sup>2+<\/jats:sup>\n                      -driven DncV activation induces rapid bacterial cell death, thereby limiting phage replication. These findings underscore a striking parallel with mammalian cGAS-STING, where Mn\n                      <jats:sup>2+<\/jats:sup>\n                      likewise amplifies antiviral responses. By illuminating the importance of Mn\n                      <jats:sup>2+<\/jats:sup>\n                      homeostasis in bacterial phage resistance, our study broadens the understanding of bacterial innate immunity and highlights a deeply conserved mechanism across prokaryotes and eukaryotes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02758-25","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T14:00:08Z","timestamp":1765202408000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Manganese activates the CBASS immunity to protect bacteria from phage infection"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1984-9832","authenticated-orcid":false,"given":"Xiao","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0051rme32","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University","place":["Yangling, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0915-2062","authenticated-orcid":false,"given":"Yongdong","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00g3f8n09","id-type":"ROR","asserted-by":"publisher"}],"name":"Ningbo Municipal Center for Disease Control and Prevention","place":["Ningbo, 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