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

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Science  17 Aug 2018:
Vol. 361, Issue 6403, pp. 704-709
DOI: 10.1126/science.aat1022

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Liquid droplets step on the cGAS

Spontaneous partitioning of a homogeneous solution of molecules, or liquid-phase separation, underlies the formation of cellular bodies from P granules to nucleoli. Essentially, dense-phase liquid droplets act like cellular compartments. Du and Chen show that DNA binding to its cytoplasmic sensor, cyclic GMP–AMP synthase (cGAS), results in liquid droplets containing activated cGAS (see the Perspective by Ablasser). This phenomenon occurs through multivalent interactions, augmented by zinc, between DNA binding domains on cGAS and DNA in a length-dependent manner. Binding triggers a switchlike reaction that concentrates the enzyme and reactants to enhance STING-dependent interferon responses.

Science, this issue p. 704; see also p. 646

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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