STING is a direct innate immune sensor of cyclic-di-GMP

By Dara L Burdette, K. Monroe, Katia Sotelo-Troha, J. Iwig, B. Eckert, M. Hyodo, Y. Hayakawa, R. Vance. Nature, 2011

1,537 citations recorded by the source corpus.

The innate immune system detects infection by using germline-encoded receptors that are specific for conserved microbial molecules. The recognition of microbial ligands leads to the production of cytokines, such as type I interferons (IFNs), that are essential for successful pathogen elimination. Cytosolic detection of pathogen-derived DNA is one major mechanism of inducing IFN production, and this process requires signalling through TANK binding kinase 1 (TBK1) and its downstream transcription factor, IFN-regulatory factor 3 (IRF3). In addition, a transmembrane protein called STING (stimulator of IFN genes; also known as MITA, ERIS, MPYS and TMEM173) functions as an essential signalling adaptor, linking the cytosolic detection of DNA to the TBK1–IRF3 signalling axis. Recently, unique nucleic acids called cyclic dinucleotides, which function as conserved signalling molecules in bacteria, have also been shown to induce a STING-dependent type I IFN response. However, a mammalian sensor of cyclic dinucleotides has not been identified. Here we report evidence that STING itself is an innate immune sensor of cyclic dinucleotides. We demonstrate that STING binds directly to radiolabelled cyclic diguanylate monophosphate (c-di-GMP), and we show that unlabelled cyclic dinucleotides, but not other nucleotides or nucleic acids, compete with c-di-GMP for binding to STING. Furthermore, we identify mutations in STING that selectively affect the response to cyclic dinucleotides without affecting the response to DNA. Thus, STING seems to function as a direct sensor of cyclic dinucleotides, in addition to its established role as a signalling adaptor in the IFN response to cytosolic DNA. Cyclic dinucleotides have shown promise as novel vaccine adjuvants and immunotherapeutics, and our results provide insight into the mechanism by which cyclic dinucleotides are sensed by the innate immune system.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/7ababf7a2daad547c06a35b9d3251d730c613167

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Citations in the corpus

Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High Affinity Ligand for STING (2013, positive): “…(CTD) encompassing residues 139–379 of human STING, which was previously shown to mediate binding to the bacterial second messenger cyclic diGMP (Burdette et al., 2011; Huang et al., 2012; Ouyang et al., 2012; Shang et al., 2012; Shu et al., 2012; Yin et al., 2012), was expressed in E. coli…”
STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors (2014, background): “STING has been shown to function as an adaptor molecule for DNA recognition pathways and likely occurs indirectly through binding of cyclic dinucleotides generated by the enzyme cGAS (Abe et al., 2013; Burdette et al., 2011;Wu et al., 2013).”
STING: infection, inflammation and cancer (2015, positive): “Stimulator of interferon genes (STING; also known as MITA and MPYS, and encoded by TMEM173) is a signalling molecule associated with the endoplasmic reticulum (ER) and is essential for controlling the transcription of numerous host defence genes, including type I interferons (IFNs) and pro-inflammat”
cGAS in action: Expanding roles in immunity and inflammation (2019, background): “Although this review focuses on self-DNA sensing and the effects of the endogenous cyclic dinucleotide cGAMP, STING can also directly become engaged by prokaryotic cyclic dinucleotides, containing two 3′-5′-phosphodiester linkages (3′3′-CDNs) (26).”