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

Science ◽  
2018 ◽  
Vol 361 (6403) ◽  
pp. 704-709 ◽  
Author(s):  
Mingjian Du ◽  
Zhijian J. Chen

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.

2017 ◽  
Vol 86 (1) ◽  
pp. 541-566 ◽  
Author(s):  
Kazuki Kato ◽  
Hiroki Omura ◽  
Ryuichiro Ishitani ◽  
Osamu Nureki

Science ◽  
2012 ◽  
Vol 339 (6121) ◽  
pp. 826-830 ◽  
Author(s):  
J. Wu ◽  
L. Sun ◽  
X. Chen ◽  
F. Du ◽  
H. Shi ◽  
...  

2007 ◽  
Vol 27 (21) ◽  
pp. 7451-7461 ◽  
Author(s):  
Jessica E. Hutti ◽  
Benjamin E. Turk ◽  
John M. Asara ◽  
Averil Ma ◽  
Lewis C. Cantley ◽  
...  

ABSTRACT Misregulation of NF-κB signaling leads to infectious, inflammatory, or autoimmune disorders. IκB kinase β (IKKβ) is an essential activator of NF-κB and is known to phosphorylate the NF-κB inhibitor, IκBα, allowing it to undergo ubiquitin-mediated proteasomal degradation. However, beyond IκBα, few additional IKKβ substrates have been identified. Here we utilize a peptide library and bioinformatic approach to predict likely substrates of IKKβ. This approach predicted Ser381 of the K63 deubiquitinase A20 as a likely site of IKKβ phosphorylation. While A20 is a known negative regulator of innate immune signaling pathways, the mechanisms regulating the activity of A20 are poorly understood. We show that IKKβ phosphorylates A20 in vitro and in vivo at serine 381, and we further show that this phosphorylation event increases the ability of A20 to inhibit the NF-κB signaling pathway. Phosphorylation of A20 by IKKβ thus represents part of a novel feedback loop that regulates the duration of NF-κB signaling following activation of innate immune signaling pathways.


Sign in / Sign up

Export Citation Format

Share Document