Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway

L Sun, J Wu, F Du, X Chen, ZJ Chen - Science, 2013 - science.org
L Sun, J Wu, F Du, X Chen, ZJ Chen
Science, 2013science.org
The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers
host immune responses such as the production of type I interferons. Cytosolic DNA induces
interferons through the production of cyclic guanosine monophosphate–adenosine
monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor
protein STING. Through biochemical fractionation and quantitative mass spectrometry, we
identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family …
The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.
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