Molecular Cell
Volume 51, Issue 2, 25 July 2013, Pages 226-235
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Article
Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High-Affinity Ligand for STING

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Highlights

  • 2′3′-cGAMP is an endogenous second messenger produced by mammalian cells

  • 2′3′-cGAMP is a high-affinity ligand for STING

  • 2′3′-cGAMP is a potent inducer of type I interferons

  • 2′3′-cGAMP binding induces conformational changes of STING

Summary

The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2′-OH of GMP and 5′-phosphate of AMP, and the other between 3′-OH of AMP and 5′-phosphate of GMP. This molecule, termed 2′3′-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2′3′-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation.

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These authors contributed equally to this work