Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA.

Abstract

Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity. This DNA signaling pathway requires the adaptor protein STING and the transcription factor IRF3, but the mechanism of DNA sensing is unclear. We found that mammalian cytosolic extracts synthesized cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP) in vitro from adenosine triphosphate and guanosine triphosphate in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-β. Thus, cGAMP functions as an endogenous second messenger in metazoans and triggers interferon production in response to cytosolic DNA.

• Authors: Jiaxi Wu, Lijun Sun, Xiang Chen, Fenghe Du, Heping Shi, Chuo Chen, Zhijian J Chen
• Journal: Science (New York, N.Y.) (Science) Vol. 339 Issue 6121 Pg. 826-30 (Feb 15 2013) ISSN: 1095-9203 [Electronic] United States
• PMID: 23258412 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Extracts
• Interferon Regulatory Factor-3
• Membrane Proteins
• Nucleotides, Cyclic
• STING1 protein, human
• cyclic guanosine monophosphate-adenosine monophosphate
• Interferon-beta
• DNA
• Cyclic AMP
• Cyclic GMP

Topics

• Animals
• Cell Extracts (chemistry)
• Cell Line
• Cyclic AMP (metabolism)
• Cyclic GMP (metabolism)
• Cytosol (immunology)
• DNA (immunology)
• HEK293 Cells
• Herpesvirus 1, Human (immunology)
• Humans
• Immunity, Innate
• Interferon Regulatory Factor-3 (metabolism)
• Interferon-beta (biosynthesis)
• Membrane Proteins (genetics, metabolism)
• Mice
• Nucleotides, Cyclic (metabolism)
• RNA Interference
• Second Messenger Systems (immunology)
• Transfection