瑞士苏黎世大学Martin Jinek等研究人员，合作揭示了Shedu抗噬菌体防御系统的DNA末端感知与切割。相关论文于2024年12月31日发表在《细胞》杂志上。

研究人员报告了apo型和双链DNA（dsDNA）结合的四聚体SduA组装的冷冻电子显微镜（cryo-EM）结构，进而揭示了SduA的N端结构域形成一个夹具，能够识别自由的DNA末端。

末端结合将DNA定位于PD-(D/E)XK核酸酶域上，导致在距离5′末端固定的距离处发生双链DNA断裂。Shedu的末端定向DNA断裂活性防止了线性DNA在体内的传播。最后，研究人员展示了，噬菌体通过抑制其依赖重组的DNA复制途径逃避Shedu免疫。

综上所述，这些结果定义了Shedu系统的抗病毒机制，并强调了识别病原特异性核酸结构，是固有免疫跨所有生命领域的保守特征。

据了解，识别与入侵病原相关的分子模式，是固有免疫系统的标志。原核生物在固有抗噬菌体免疫中，部署了复杂的宿主防御机制。Shedu是一个单一成分的防御系统，包含一个假定的核酸酶SduA。

附：英文原文

Title: DNA end sensing and cleavage by the Shedu anti-phage defense system

Author: Luuk Loeff, Alexander Walter, Gian Tizio Rosalen, Martin Jinek

Issue&Volume: 2024-12-31

Abstract: 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.

DOI: 10.1016/j.cell.2024.11.030

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01346-1