3'3'-cGAMP - STING Agonist

3'3'-cGAMP bacterial cyclic di-nucleotide - STING ligand

3’3’-cGAMP (cyclic [G(3’,5’)pA(3’,5’)p], previously known as cGAMP) is a cyclic di-nucleotide produced by bacteria. 3’3’-cGAMP is also referred to as "canonical" cGAMP due the presence of the classical 3’-5’ phosphodiester linkages between the guanosine and the adenosine.

Recently, 3’3’-cGAMP was reported to bind STING (stimulator of IFN genes) and subsequently induce TBK1-IRF3-dependent production of IFN-β [1]. Studies in bacteria revealed that 3’3’-cGAMP serves as a second messenger and plays a role in bacterial chemotaxis and colonization [2].

Structural and functional studies revealed that the canonical 3’3’-cGAMP produced by bacteria is distinct from the noncanonical 2’3’-cGAMP produced by mammalian cGAS [3]. Certain variants of STING are able to distinguish between canonical and noncanonical cGAMP [4].

3’3’-cGAMP is more potent in activating IRF3 than c-di-AMP and c-diGMP, other 3',5' cyclic dinucleotides that also bind to STING [5].

References

1. Zhang X. et al., 2013. Cyclic GMP-AMP containing mixed phosphdiester linkages is an endogenous high-affinity ligand for STING. Mol Cell.51(2):226-35.
2. Davies B. et al., 2012. Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell. 149(2):358-70.)
3. Gao P. et al., 2013. Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 153(5):1094-107.
4. Diner E. et al., 2013. The Innate Immune DNA Sensor cGAS Produces a Noncanonical Cyclic Dinucleotide that Activates Human STING. Cell Rep. 3(5):1355-61.
5. Burdette D. et al., 2011. STING is a direct innate immune sensor of cyclic di-GMP. Nature. 478(7370):515-8.