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Crystal structure of the QatD nuclease from the Qat anti-phage system
Structural highlights
Publication Abstract from PubMedSir2-HerA systems are abortive infection defenses that integrate multiple enzymatic activities to induce growth arrest, thereby limiting phage propagation. However, the molecular logic that couples phage sensing to a precisely gated antiviral response, thereby ensuring infection-specific activation, remains unclear. Through genomic mining of Escherichia coli, we show that E. coli Sir2-HerA immunity diversifies into functional subtypes and identify three types (I-III) with distinct protection profiles. Focusing on the most potent type III system, we identified its phage activators, Gp2.5 and Gp5.9, through an unbiased T7 proteome screen. Mechanistically, type III Sir2-HerA follows a multilayered gating logic. Phage proteins trigger both the HerA nickase and Sir2 NADase; however, the activated NADase remains dormant due to an ATP-mediated checkpoint. The HerA nickase introduces DNA nicks, leading to the accumulation of end-exposed DNA intermediates that engage the complex-associated ATPase to drive ATP consumption. This process relieves the checkpoint, thereby unleashing the full trigger-dependent NADase activity and enabling robust NAD+ depletion. Together, our findings reveal a sophisticated molecular logic that integrates diverse enzymatic activities into a tiered gating architecture, ensuring high-fidelity phage defense while preventing inadvertent activation. Classification of Sir2-HerA systems reveals a multilayered regulatory cascade gating the type III antiphage activity.,Zhang X, Han J, Wang S, Sun E, Xia Z, Li M, Kuang S, Song H, Li G, Ding X, Zou T, Chen M, Tao P Nucleic Acids Res. 2026 Jul 17;54(14):gkag746. doi: 10.1093/nar/gkag746. PMID:42549578[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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