The innate immune DNA Sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING.
Open accessAbstract
The presence of foreign DNA in the cytosol of mammalian cells elicits a potent antiviral interferon response. Recently, cytosolic DNA was proposed to induce the synthesis of cyclic GMP-AMP (cGAMP) upon binding to an enzyme called cGAMP synthase (cGAS). cGAMP activates an interferon response by binding to a downstream receptor called STING. Here, we identify natural variants of human STING (hSTING) that are poorly responsive to cGAMP yet, unexpectedly, are normally responsive to DNA and cGAS signaling. We explain this paradox by demonstrating that the cGAS product is actually a noncanonical cyclic dinucleotide, cyclic [G(2'-5')pA(3'-5')p], which contains a single 2'-5' phosphodiester bond. Cyclic [G(2'-5')pA(3'-5')p] potently activates diverse hSTING receptors and, therefore, may be a useful adjuvant or immunotherapeutic. Our results indicate that hSTING variants have evolved to distinguish conventional (3'-5') cyclic dinucleotides, known to be produced mainly by bacteria, from the noncanonical cyclic dinucleotide produced by mammalian cGAS.
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cGAS is a 522 amino acid protein, cytosolic DNA sensor that activates innate immunity upon sensing aberrant dsDNA irrespective of source.
“cGAS a 522 amino acid protein, is a cytosolic DNA sensor that activates innate immunity upon sensing aberrant double stranded (ds) DNA molecules irrespective of the source.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Diner et al., 2013
STING recruits TBK1 and IKK.
“STING recruits TANK-binding kinase 1 (TBK1) and IK-B kinase (IKK) (Ablasser et al., 2013; Diner et al., 2013; Gao et al., 2013; Sun et al., 2013, 2018; Wu et al., 2013; Zhang et al., 2013; Ablasser and Gulen, 2016; Chen et al., 2016).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Diner et al., 2013
In presence of ATP and GTP, cGAS catalyzes production of 2′3′ cGAMP which stimulates STING.
“In the presence of ATP and GTP, cGAS catalyzes the production of 2′3′ cyclic GMP-AMP (cGAMP) which stimulates the adaptor protein, STING.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Diner et al., 2013
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- Authors
- Diner, E. J., Burdette, D. L., Wilson, S. C., Monroe, K. M., Kellenberger, C. A., Hyodo, M., Hayakawa, Y., Hammond, M. C., & Vance, R. E.
- Affiliations
- University of California, Berkeley (US)
- Hokkaido University (JP)
- Aichi Institute of Technology (JP)
- Corresponding author
- Hammond, Ming C.
- Vance, Russell E.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 3
- Issue
- 5
- Pages
- 1355-1361
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3706192
- OpenAlex
- W2055063197
- Cited by
- 767
- References
- 29
- Citations by year
- 2026: 52 · 2025: 56 · 2024: 72 · 2023: 57 · 2022: 60 · 2021: 65 · 2020: 85 · 2019: 68 · 2018: 47 · 2017: 54 · 2016: 41 · 2015: 41 · 2014: 45 · 2013: 24
- FWCI
- 27.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1dp2od008677-01)
- Japan Society for the Promotion of Science (24350087)
- National Institute of General Medical Sciences (T32GM066698)
- National Institute of Allergy and Infectious Diseases (AI063302, R21AI103817, AI075039, AI080749, R01AI080749, AI103817, 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
- cGAS, STING, cyclic dinucleotides, cGAMP, innate immunity, cytosolic DNA sensing, interferon response, adjuvants, immunotherapy
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Base Sequence, Cell Line, Humans, Immunity, Innate, Membrane Proteins, Molecular Sequence Data, Nucleotides, Cyclic, Nucleotidyltransferases, Oligonucleotides, Protein Binding, RNA Interference, RNA, Small Interfering, Mice, HEK293 Cells
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