Cyclic Dinucleotides Get Stung

Science Signaling  01 Nov 2011:
Vol. 4, Issue 197, pp. ec303
DOI: 10.1126/scisignal.4197ec303

As part of the innate immune response, specific receptors in host cells detect distinct microbial components and stimulate the production of type I interferon (IFN) and other cytokines to kill the invading pathogen. The detection of cytosolic microbial DNA through a pathway that activates the transcription factor IFN regulatory factor 3 depends on the adaptor protein STING (stimulator of IFN genes). Cyclic dinucleotides, such as cyclic diguanylate monophosphate (c-di-GMP), are signaling molecules produced by bacteria, and they trigger IFN production in a STING-dependent manner, but the direct sensor involved was not known. Burdette et al. performed experiments in transfected human embryonic kidney (HEK) 293 cells, which do not respond to c-di-GMP, to identify the innate immune components that enabled the cells to produce IFN in response to the cyclic dinucleotide. They found that STING was sufficient to elicit a cellular response to c-di-GMP but not to DNA. Experiments with radiolabeled c-di-GMP and tagged STING protein showed that c-di-GMP bound directly to STING and that unlabeled cyclic dinucleotides, but not other nucleic acids, competed with labeled c-di-GMP for binding to STING. Binding of c-di-GMP to STING occurred through the C-terminal domain of the protein, and one molecule of c-di-GMP bound to two molecules of STING. Mutations in STING that prevented its binding to c-di-GMP also blocked induction of the IFN response to the cyclic dinucleotide. Another mutant STING protein induced an IFN response to DNA but not to c-di-GMP, suggesting that both pathways share STING as a component. Together, these data suggest an extended role for STING in the cellular response to microbial infection through its direct sensing of bacterial cyclic dinucleotides.

D. L. Burdette, K. M. Monroe, K. Sotelo-Troha, J. S. Iwig, B. Eckert, M. Hyodo, Y. Hayakawa, R. E. Vance, STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515–518 (2011). [PubMed]