State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China.
Nucleic Acids Res. 2021 Dec 2;49(21):12306-12319. doi: 10.1093/nar/gkab1121.
DNA damage and apoptosis lead to the release of free nucleosomes-the basic structural repeating units of chromatin-into the blood circulation system. We recently reported that free nucleosomes that enter the cytoplasm of mammalian cells trigger immune responses by activating cGMP-AMP synthase (cGAS). In the present study, we designed experiments to reveal the mechanism of nucleosome uptake by human cells. We showed that nucleosomes are first absorbed on the cell membrane through nonspecific electrostatic interactions between positively charged histone N-terminal tails and ligands on the cell surface, followed by internalization via clathrin- or caveolae-dependent endocytosis. After cellular internalization, endosomal escape occurs rapidly, and nucleosomes are released into the cytosol, maintaining structural integrity for an extended period. The efficient endocytosis of extracellular nucleosomes suggests that circulating nucleosomes may lead to cellular disorders as well as immunostimulation, and thus, the biological effects exerted by endocytic nucleosomes should be addressed in the future.
DNA 损伤和细胞凋亡导致游离核小体（染色质的基本结构重复单位）释放到血液循环系统中。我们最近报道称，进入哺乳动物细胞质的游离核小体通过激活 cGMP-AMP 合酶（cGAS）触发免疫反应。在本研究中，我们设计实验来揭示核小体被人类细胞摄取的机制。我们表明，核小体首先通过带正电荷的组蛋白 N 端尾巴与细胞表面配体之间的非特异性静电相互作用吸附在细胞膜上，然后通过网格蛋白或小窝依赖的内吞作用内化。细胞内吞作用后，内体逃逸迅速发生，核小体释放到细胞质中，在较长时间内保持结构完整性。细胞外核小体的有效内吞作用表明，循环核小体可能导致细胞紊乱和免疫刺激，因此，未来应该研究内吞核小体发挥的生物学效应。
