Histones are traditionally recognized for structuring nuclear architecture and regulating gene expression. Recent advances have revealed their roles in inflammation, coagulation, and immune responses, where they act as damage-associated molecular patterns. The mechanisms by which histones induce membrane leakage are not well understood, and certain cells, including endothelial cells and peritoneal macrophages, show resistance to histone-mediated pore formation. We utilized liposome leakage assays to explore the pore-forming capabilities of different histone configurations, including individual histones, tail regions, and globular domains. Our results demonstrate that globular domains primarily drive pore formation. Using cytotoxicity assays, we further demonstrate that the globular domain of extracellular histones is primarily implicated in inducing lytic cell death. This study provides insights into the pathological roles of histones and suggests potential therapeutic targets to mitigate their harmful effects.

中文翻译：

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细胞外组蛋白的球状结构域通过膜破坏机制介导细胞毒性


传统上，组蛋白被认为用于构建核结构和调节基因表达。最近的进展揭示了它们在炎症、凝血和免疫反应中的作用，它们充当与损伤相关的分子模式。组蛋白诱导膜渗漏的机制尚不清楚，某些细胞（包括内皮细胞和腹膜巨噬细胞）对组蛋白介导的孔形成表现出抵抗力。我们利用脂质体泄漏测定来探索不同组蛋白配置的成孔能力，包括单个组蛋白、尾部区域和球状结构域。我们的结果表明，球状结构域主要驱动孔的形成。使用细胞毒性测定，我们进一步证明细胞外组蛋白的球状结构域主要与诱导裂解细胞死亡有关。这项研究提供了对组蛋白病理作用的见解，并提出了减轻其有害影响的潜在治疗靶点。