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Science. 2018 Aug 17;361(6403):704-709. doi: 10.1126/science.aat1022. Epub 2018 Jul 5.

DNA-induced liquid phase condensation of cGAS activates innate immune signaling.

Du M1,2, Chen ZJ3,2,4.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
2
Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
3
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. zhijian.chen@utsouthwestern.edu.
4
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.

Abstract

The binding of DNA to cyclic GMP-AMP synthase (cGAS) leads to the production of the secondary messenger cyclic GMP-AMP (cGAMP), which activates innate immune responses. We have shown that DNA binding to cGAS robustly induced the formation of liquidlike droplets in which cGAS was activated. The disordered and positively charged cGAS N terminus enhanced cGAS-DNA phase separation by increasing the valencies of DNA binding. Long DNA was more efficient in promoting cGAS liquid phase separation and cGAS enzyme activity than short DNA. Moreover, free zinc ions enhanced cGAS enzyme activity both in vitro and in cells by promoting cGAS-DNA phase separation. These results demonstrated that the DNA-induced phase transition of cGAS promotes cGAMP production and innate immune signaling.

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PMID:
29976794
DOI:
10.1126/science.aat1022
[Indexed for MEDLINE]

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