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Updated: Jun 3, 2026
Hybrid Ensemble and Single-molecule Assay to Image the Motion of Fully Reconstituted CMG
Published on: July 26, 2024
Electrostatic bimodality of human cytosolic DNA sensor cGAS-dsDNA condensates revealed by millisecond flashing
Xiaoting Ling1,2, Xingrui Song1,2, Dapeng Zhang1,2,3
1State Key Laboratory of Environmental Chemistry and Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
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.
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