毫秒闪光电泳分离揭示了人细胞质DNA传感器cGAS-dsDNA缩合物的静电双峰性
Electrostatic bimodality of human cytosolic DNA sensor cGAS-dsDNA condensates revealed by millisecond flashing electrophoretic separation.
摘要(中文译文)
生物分子凝聚体内的静电景观是调控其结构稳定性与功能可塑性的关键因素。为定量解析这些难以捕捉的电学特征，我们开发了毫秒级闪式电泳分离（msFES）平台，可在纳升级尺度上以接近单液滴分辨率对生物分子凝聚体进行表征，重点聚焦于zeta电位（zeta potential）的刻画。将msFES应用于人源胞质DNA感受器cGAS（hcGAS）与DNA形成的凝聚体时，我们意外发现了一种内在的静电异质性：由相同组分在相同条件下形成的液滴呈现出两个截然不同的zeta电位群体。这种异质性决定了对TREX1的差异化敏感性——TREX1是一种外切核酸酶，可选择性解体带负电荷的液滴，而对带正电荷的组装体则不予作用甚至使其扩增，从而可能调控cGAS的激活。致病性hcGAS变异体（K432T、G303E）破坏了这一静电调控，使hcGAS-DNA液滴对TREX1介导的DNA降解高度敏感。因此，msFES揭示了相分离系统中一个隐藏的基于电荷的调控层面，可能将凝聚体生物物理学与先天免疫调控联系起来。
Abstract
Electrostatic landscapes within biomolecular condensates are critical regulators of their structural stability and functional plasticity. To quantitatively resolve these elusive electrical signatures, we develop a millisecond Flashing Electrophoretic Separation (msFES) platform enabling nanoliter-scale profiling of biomolecular condensates at near single-droplet resolution-with a focus on zeta potential characterization. Applying msFES to condensates formed by human cytosolic DNA sensor cGAS (hcGAS) and DNA, we unexpectedly discover an intrinsic electrostatic heterogeneity: droplets formed from identical components under identical conditions exhibit two distinct zeta-potential populations. This heterogeneity dictates differential susceptibility to TREX1, an exonuclease that selectively disassembles negatively charged droplets while sparing or amplifying positively charged assemblies, thereby potentially modulating cGAS activation. Pathogenic hcGAS variants (K432T, G303E) disrupt this electrostatic control, rendering hcGAS-DNA droplets hypersensitive to TREX1-mediated DNA degradation. msFES thus uncovers a hidden layer of charge-based regulation in phase-separated systems, potentially linking condensate biophysics to innate immune control.
如何引用
AMA
Xiaoting Ling, Xingrui Song, Dapeng Zhang, Weiyi Lai, Cong Liu, Guibin Jiang, et al. Electrostatic bimodality of human cytosolic DNA sensor cGAS-dsDNA condensates revealed by millisecond flashing electrophoretic separation.. Nature communications. 2026; doi:10.1038/s41467-026-73740-7.
APA
Xiaoting Ling, Xingrui Song, Dapeng Zhang, Weiyi Lai, Cong Liu, Guibin Jiang, et al (2026). Electrostatic bimodality of human cytosolic DNA sensor cGAS-dsDNA condensates revealed by millisecond flashing electrophoretic separation.. Nature communications. https://doi.org/10.1038/s41467-026-73740-7
GB/T 7714
Xiaoting Ling, Xingrui Song, Dapeng Zhang, Weiyi Lai, Cong Liu, Guibin Jiang, et al. Electrostatic bimodality of human cytosolic DNA sensor cGAS-dsDNA condensates revealed by millisecond flashing electrophoretic separation.[J]. Nature communications, 2026 doi:10.1038/s41467-026-73740-7.
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