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Science 339 (6121): 786-791

Copyright © 2013 by the American Association for the Advancement of Science

Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway

Lijun Sun,1,2,* Jiaxi Wu,1,* Fenghe Du,1,2 Xiang Chen,1,2 Zhijian J. Chen1,2,{dagger}

Abstract: 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.

1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: zhijian.chen{at}utsouthwestern.edu

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