mBio · 2025
Manganese activates the CBASS immunity to protect bacteria from phage infection.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Wang Xiao, Li Yongdong, Wang Xiao, Zhang Wenjing, Liu Muohua, Hao Xinwei, Chen Shukun, Chang Tianyuan, Wu Conghui, Hao Chonghua, Song Li, Ni Hongxia, Chen Yi, Shen Xihui, Xu Lei
Аннотация
UNLABELLED: The cyclic-oligonucleotide-based antiphage signaling system (CBASS) is essential for bacterial defense against phage infections, mirroring many features of the eukaryotic cGAS-STING pathway. 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 (Mn2+) serves as a key cofactor to enhance CBASS activation. Upon phage infection, the intracellular Mn2+ level is elevated, and the gene expression of the Mn2+ transportation system is upregulated. We found that Mn2+ directly augments the activity of DncV, markedly boosting 3'3'-cGAMP production. Consequently, the phospholipase CapV is activated more rapidly, driving premature bacterial cell lysis and curtailing phage replication. Notably, Mn2+ 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 Mn2+ confers bacterial resistance to phages, mirroring the Mn2+-enhanced antiviral responses of mammalian cGAS-STING.
IMPORTANCE: 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 (Mn2+) acts as a pivotal cofactor for CBASS, directly enhancing the activity of the cGAS-like cyclase DncV to generate 3'3'-cGAMP, which, in turn, activates the phospholipase CapV. This Mn2+-driven DncV activation induces rapid bacterial cell death, thereby limiting phage replication. These findings underscore a striking parallel with mammalian cGAS-STING, where Mn2+ likewise amplifies antiviral responses. By illuminating the importance of Mn2+ homeostasis in bacterial phage resistance, our study broadens the understanding of bacterial innate immunity and highlights a deeply conserved mechanism across prokaryotes and eukaryotes.
IMPORTANCE: 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 (Mn2+) acts as a pivotal cofactor for CBASS, directly enhancing the activity of the cGAS-like cyclase DncV to generate 3'3'-cGAMP, which, in turn, activates the phospholipase CapV. This Mn2+-driven DncV activation induces rapid bacterial cell death, thereby limiting phage replication. These findings underscore a striking parallel with mammalian cGAS-STING, where Mn2+ likewise amplifies antiviral responses. By illuminating the importance of Mn2+ homeostasis in bacterial phage resistance, our study broadens the understanding of bacterial innate immunity and highlights a deeply conserved mechanism across prokaryotes and eukaryotes.