Zhang Zhiying, Todeschini Thomas C, Wu Yi, Kogay Roman, Naji Ameena, Cardenas Rodriguez Joaquin, Mondi Rupavidhya, Kaganovich Daniel, Taylor David W, Bravo Jack P K, Teplova Marianna, Amen Triana, Koonin Eugene V, Patel Dinshaw J, Nobrega Franklin L
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Interdisciplinary Life Sciences Graduate Programs, Austin, TX 78712, USA; Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, TX 78712, USA.
School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK.
Cell. 2025 Jul 23. doi: 10.1016/j.cell.2025.07.002.
Bacteria and archaea deploy diverse antiviral defense systems, many of which remain mechanistically uncharacterized. Here, we characterize Kiwa, a widespread two-component system composed of the transmembrane sensor KwaA and the DNA-binding effector KwaB. Cryogenic electron microscopy (cryo-EM) analysis reveals that KwaA and KwaB assemble into a large, membrane-associated supercomplex. Upon phage binding, KwaA senses infection at the membrane, leading to KwaB binding of ejected phage DNA and inhibition of replication and late transcription, without inducing host cell death. Although KwaB can bind DNA independently, its antiviral activity requires association with KwaA, suggesting spatial or conformational regulation. We show that the phage-encoded DNA-mimic protein Gam directly binds and inhibits KwaB but that co-expression with the Gam-targeted RecBCD system restores protection by Kiwa. Our findings support a model in which Kiwa coordinates membrane-associated detection of phage infection with downstream DNA binding by its effector, forming a spatially coordinated antiviral mechanism.
细菌和古菌部署了多种抗病毒防御系统，其中许多系统的作用机制仍未得到表征。在这里，我们对Kiwa进行了表征，它是一种广泛存在的双组分系统，由跨膜传感器KwaA和DNA结合效应器KwaB组成。低温电子显微镜（cryo-EM）分析表明，KwaA和KwaB组装成一个与膜相关的大型超复合物。噬菌体结合后，KwaA在膜上感知感染，导致KwaB与被释放的噬菌体DNA结合，并抑制复制和晚期转录，而不会诱导宿主细胞死亡。虽然KwaB可以独立结合DNA，但其抗病毒活性需要与KwaA结合，这表明存在空间或构象调节。我们发现，噬菌体编码的DNA模拟蛋白Gam直接结合并抑制KwaB，但与靶向Gam的RecBCD系统共表达可恢复Kiwa的保护作用。我们的研究结果支持了一种模型，即Kiwa通过其效应器将膜相关的噬菌体感染检测与下游DNA结合协调起来，形成一种空间协调的抗病毒机制。
