STING is a direct innate immune sensor of cyclic di-GMP
Open accessAbstract
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.
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STING is a major pathway for the detection of immunogenic tumors and initiation of a spontaneous T cell response.
“the stimulator of interferon genes (STING) has been shown to be a major pathway for the detection of immunogenic tumors and initiation of a spontaneous T cell response18–21.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [21]
The paper’s Abstract describes STING as a sensor of cyclic dinucleotides and an adaptor in the interferon response to cytosolic DNA. Searches for immunogenic tumors, tumor detection, and spontaneous T-cell responses found no passage in our copy addressing those parts of the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredNatural and artificially synthetic cyclic dinucleotides have been developed as STING agonists for cancer immunotherapy.
“Sharing similar structures and biological characteristics with cGAMP, some natural and artificially synthetic cyclic dinucleotides (CDNs) are developed as STING agonists for cancer immunotherapy [265–267].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [266]
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- Authors
- Burdette, D. L., Monroe, K. M., Sotelo-Troha, K., Iwig, J. S., Eckert, B., Hyodo, M., Hayakawa, Y., & Vance, R. E.
- Affiliations
- University of California, Berkeley (US)
- Howard Hughes Medical Institute (US)
- Hokkaido University (JP)
- Aichi Institute of Technology (JP)
- Corresponding author
- Vance, Russell E.
- Venue
- Nature
- Published
- 2011-09-25
- Volume
- 478
- Issue
- 7370
- Pages
- 515-518
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3203314
- OpenAlex
- W2041345682
- Cited by
- 1,570
- References
- 27
- Citations by year
- 2026: 94 · 2025: 123 · 2024: 116 · 2023: 146 · 2022: 131 · 2021: 137 · 2020: 125 · 2019: 121 · 2018: 90 · 2017: 99 · 2016: 75 · 2015: 90 · 2014: 77 · 2013: 81 · 2012: 59
- FWCI
- 31.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Japan Society for the Promotion of Science (23700552)
- National Institute of Allergy and Infectious Diseases (AI063302, AI075039, AI080749, R01AI080749, F32AI091100, R37AI075039, P01AI063302, R01AI075039)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Keywords
- STING, c-di-GMP, cyclic dinucleotides, innate immune recognition, type I interferon, cytosolic DNA sensing, vaccine adjuvants, immunotherapeutics, STING agonist
- MeSH terms
- STING Protein, Adjuvants, Immunologic, Amino Acid Sequence, Animals, DNA, Cyclic GMP, Humans, Immunity, Innate, Interferons, Macrophages, Membrane Proteins, Molecular Sequence Data, Mice, HEK293 Cells
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