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STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling
Open accessAbstract
The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response-following infection with DNA and RNA viruses, for example-remain to be identified. Here we report the identification, following expression cloning, of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes. It comprises five putative transmembrane regions, predominantly resides in the endoplasmic reticulum and is able to activate both NF-kappaB and IRF3 transcription pathways to induce expression of type I interferon (IFN-alpha and IFN-beta ) and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpesvirus family, to induce IFN-beta, but did not significantly affect the Toll-like receptor (TLR) pathway. Yeast two-hybrid and co-immunoprecipitation studies indicated that STING interacts with RIG-I and with SSR2 (also known as TRAPbeta), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation. Ablation by RNA interference of both TRAPbeta and translocon adaptor SEC61beta was subsequently found to inhibit STING's ability to stimulate expression of IFN-beta. Thus, as well as identifying a regulator of innate immune signalling, our results imply a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.
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“TBK1 also activates NF‐κB to induce expression of IFN and inflammatory cytokines.65, 66, 67”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [65]
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“cGAMP produced by cGAS activation binds to STING which is located on the membrane of endoplasmic reticulum (ER)391 and leads to the translocation of STING from ER to the Golgi where it is further modified.392”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [391]
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“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 [20]
Experimental — accuracy not yet measuredIn the citing paper
“TBK1 associated with STING also facilitates dsDNA-mediated activation of NF-κB to promote proinflammatory gene transcription (Abe and Barber, 2014; Ishikawa and Barber, 2008).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Ishikawa and Barber, 2008
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Cites
Yoneyama, M., Kikuchi, M., Natsukawa, T., Shinobu, N., Imaizumi, T., Miyagishi, M., Taira, K., Akira, S., & Fujita, T. (2004) · Nature Immunology · doi:10.1038/ni1087 · Cited by 4,022
Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses
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Seth, R. B., Sun, L., Ea, C.-K., & Chen, Z. J. (2005) · Cell · doi:10.1016/j.cell.2005.08.012 · Cited by 3,329
IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction
Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K. J., Takeuchi, O., & Akira, S. (2005) · Nature Immunology · doi:10.1038/ni1243 · Cited by 2,562
5'-Triphosphate RNA Is the Ligand for RIG-I
Hornung, V., Ellegast, J., Kim, S., Brzózka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K.-K., Schlee, M., et al. (2006) · Science · doi:10.1126/science.1132505 · Cited by 2,474
Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus
Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., & Tschopp, J. (2005) · Nature · doi:10.1038/nature04193 · Cited by 2,401
RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates
Pichlmair, A., Schulz, O., Tan, C. P., Näslund, T. I., Liljeström, P., Weber, F., & Reis e Sousa, C. (2006) · Science · doi:10.1126/science.1132998 · Cited by 2,210
VISA Is an Adapter Protein Required for Virus-Triggered IFN-β Signaling
Xu, L., Wang, Y., Han, K.-J., Li, L., Zhai, Z., & Shu, H. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.08.014 · Cited by 1,849
Distinct RIG-I and MDA5 Signaling by RNA Viruses in Innate Immunity
Loo, Y.-M., Fornek, J., Crochet, N., Bajwa, G., Perwitasari, O., Martinez-Sobrido, L., Akira, S., Gill, M. A., García-Sastre, A., Katze, M. G., et al. (2008) · Journal of Virology · doi:10.1128/jvi.01080-07 · Cited by 1,071
Recognition of Cytosolic DNA Activates an IRF3-Dependent Innate Immune Response
Stetson, D. B., & Medzhitov, R. M. (2006) · Immunity · doi:10.1016/j.immuni.2005.12.003 · Cited by 1,003
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Targeting DNA Damage Response and Immune Checkpoint for Anticancer Therapy
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Dynamic STING repression orchestrates immune cell development and function
Knox, K., Jeltema, D., Dobbs, N., Yang, K., Xing, C., Song, K., Tang, Z., Torres-Ramirez, G., Wang, J., Gao, S., et al. (2025) · Science Immunology · doi:10.1126/sciimmunol.ado9933 · Cited by 23
Reappraisal of Antimalarials in Interferonopathies: New Perspectives for Old Drugs
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Metadata
- Authors
- Ishikawa, H., & Barber, G. N.
- Affiliations
- University of Miami (US)
- Corresponding author
- Barber, Glen N.
- Venue
- Nature
- Published
- 2008-08-24
- Volume
- 455
- Issue
- 7213
- Pages
- 674-678
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2804933
- OpenAlex
- W2060004514
- Semantic Scholar
- cd831bfb6fd9847baedbe5161ddd21d405728bee
- Cited by
- 3,576
- References
- 29
- Citations by year
- 2026: 310 · 2025: 394 · 2024: 359 · 2023: 332 · 2022: 322 · 2021: 315 · 2020: 270 · 2019: 195 · 2018: 163 · 2017: 161 · 2016: 115 · 2015: 118 · 2014: 112 · 2013: 123 · 2012: 83
- FWCI
- 28.23
- Type
- journal article
- Language
- en
- Update notices
- erratum (2008-11-13)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI079336)
- 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 › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- STING, endoplasmic reticulum, innate immunity, interferon-beta, IRF3, NF-κB, RIG-I, Sec61β, translocon, TRAP complex, vesicular stomatitis virus, herpesvirus, negative-strand RNA viruses, viral DNA sensing, antiviral defense, protein translocation, pattern recognition receptors
- MeSH terms
- STING Protein, Animals, Cell Line, Endoplasmic Reticulum, Fibroblasts, Humans, Immunity, Innate, Interferons, Membrane Proteins, Mice, Inbred C57BL, Signal Transduction, Mice, Knockout, Mice
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