Loeff Luuk, Walter Alexander, Rosalen Gian Tizio, Jinek Martin
Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Cell. 2025 Feb 6;188(3):721-733.e17. doi: 10.1016/j.cell.2024.11.030. Epub 2024 Dec 31.
The detection of molecular patterns associated with invading pathogens is a hallmark of innate immune systems. Prokaryotes deploy sophisticated host defense mechanisms in innate anti-phage immunity. Shedu is a single-component defense system comprising a putative nuclease SduA. Here, we report cryoelectron microscopy (cryo-EM) structures of apo- and double-stranded DNA (dsDNA)-bound tetrameric SduA assemblies, revealing that the N-terminal domains of SduA form a clamp that recognizes free DNA ends. End binding positions the DNA over the PD-(D/E)XK nuclease domain, resulting in dsDNA nicking at a fixed distance from the 5' end. The end-directed DNA nicking activity of Shedu prevents propagation of linear DNA in vivo. Finally, we show that phages escape Shedu immunity by suppressing their recombination-dependent DNA replication pathway. Taken together, these results define the antiviral mechanism of Shedu systems, underlining the paradigm that recognition of pathogen-specific nucleic acid structures is a conserved feature of innate immunity across all domains of life.
检测与入侵病原体相关的分子模式是先天免疫系统的一个标志。原核生物在先天抗噬菌体免疫中部署了复杂的宿主防御机制。Shedu是一种单组分防御系统，由一种假定的核酸酶SduA组成。在这里，我们报告了无apo和双链DNA（dsDNA）结合的四聚体SduA组装体的冷冻电子显微镜（cryo-EM）结构，揭示了SduA的N端结构域形成一个识别游离DNA末端的夹子。末端结合将DNA定位在PD-（D/E）XK核酸酶结构域上方，导致dsDNA在距5'端固定距离处切口。Shedu的末端定向DNA切口活性可防止线性DNA在体内传播。最后，我们表明噬菌体通过抑制其重组依赖性DNA复制途径来逃避Shedu免疫。综上所述，这些结果定义了Shedu系统的抗病毒机制，强调了识别病原体特异性核酸结构是生命所有领域先天免疫的一个保守特征这一范式。
