Burn Garth Lawrence, Raisch Tobias, Tacke Sebastian, Winkler Moritz, Prumbaum Daniel, Thee Stephanie, Gimber Niclas, Raunser Stefan, Zychlinsky Arturo
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.
Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
Nature. 2025 Sep 17. doi: 10.1038/s41586-025-09523-9.
Neutrophils, the most abundant and biotoxic immune cells, extrude nuclear DNA into the extracellular space to maintain homeostasis. Termed neutrophil extracellular traps (NETs), these protein-modified and decondensed extracellular DNA scaffolds control infection and are involved in coagulation, autoimmunity and cancer. Here we show how myeloperoxidase (MPO), a highly expressed neutrophil protein, disassembles nucleosomes, thereby facilitating NET formation, yet also binds stably to NETs extracellularly. We describe how the oligomeric status of MPO governs both outcomes. MPO dimers interact with nucleosomal DNA using one protomer and concurrently dock into the nucleosome acidic patch with the other protomer. As a consequence, dimeric MPO displaces DNA from the core complex, culminating in nucleosome disassembly. On the other hand, MPO monomers stably interact with the nucleosome acidic patch without making concomitant DNA contacts, explaining how monomeric MPO binds to and licences NETs to confer hypohalous acid production in the extracellular space. Our data demonstrate that the binding of MPO to chromatin is governed by specific molecular interactions that transform chromatin into a non-replicative, non-encoding state that offers new biological functions in a cell-free manner. We propose that MPO is, to our knowledge, the first member of a class of proteins that convert chromatin into an immune effector.
中性粒细胞是数量最多且具有生物毒性的免疫细胞，它们将核DNA挤出到细胞外空间以维持体内平衡。这些蛋白质修饰且解聚的细胞外DNA支架被称为中性粒细胞胞外陷阱（NETs），可控制感染，并参与凝血、自身免疫和癌症过程。在这里，我们展示了髓过氧化物酶（MPO）这种高表达的中性粒细胞蛋白如何拆解核小体，从而促进NET的形成，同时它还能在细胞外与NETs稳定结合。我们描述了MPO的寡聚状态如何决定这两种结果。MPO二聚体用一个原体与核小体DNA相互作用，同时用另一个原体对接进入核小体酸性补丁。结果，二聚体MPO将DNA从核心复合物中置换出来，最终导致核小体拆解。另一方面，MPO单体与核小体酸性补丁稳定相互作用，而不与DNA同时接触，这解释了单体MPO如何结合并许可NETs在细胞外空间产生次卤酸。我们的数据表明，MPO与染色质的结合受特定分子相互作用的支配，这些相互作用将染色质转化为一种非复制、非编码状态，以无细胞方式提供新的生物学功能。据我们所知，我们提出MPO是一类将染色质转化为免疫效应物的蛋白质中的首个成员。
