Myeloperoxidase transforms chromatin into neutrophil extracellular traps

• 成果类型: Article
• 署名作者: Burn, Garth Lawrence; Raisch, Tobias; Tacke, Sebastian; Winkler, Moritz; Prumbaum, Daniel; Thee, Stephanie; Gimber, Niclas; Raunser, Stefan; Zychlinsky, Arturo
• 署名单位: Max Planck Society; Max Planck Society; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09523-9
• 发表日期: 2025-11-20
• 关键词: histone octamer; nucleosome; RECOGNITION; mechanism; bacterial; elastase; complex; binding; heme

摘要

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 cancer1,2. 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 space3. 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.