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

By Mingjian Du, Zhijian J. Chen. Science, 2018

920 citations recorded by the source corpus.

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 DNA sensor cGAS forms liquid droplets that stimulate innate immune responses. 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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d20534010a3cb074b04c5128f2b4fb5cc7a9131a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. A. Ablasser
2. Zhijian J. Chen
3. Shizuo Akira
4. N. Perkins
5. Tuo Li
6. G. Barber
7. Ivan Dikic
8. Taro Kawai

In Molecular Biology

1. A. Ablasser
2. Zhijian J. Chen
3. D. Dormann
4. S. Alberti

Citations in the corpus

• Liquid-Liquid Phase Separation in Disease. (2019, background): “Phase separation activates cGAS and this leads to the production of the second messenger cyclic GMP-AMP (cGAMP) and the induction of the innate immune response (46).”
• cGAS in action: Expanding roles in immunity and inflammation (2019, background): “Together, both domains bind to dsDNA through multivalent interactions, which drive the liquid–liquid phase separation of cGAS and DNA (18).”