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STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
Open accessAbstract
The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN). However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection. Murine embryonic fibroblasts, as well as antigen presenting cells such as macrophages and dendritic cells (exposed to intracellular B-form DNA, the DNA virus herpes simplex virus 1 (HSV-1) or bacteria Listeria monocytogenes), were found to require STING to initiate effective IFN production. Accordingly, Sting-knockout mice were susceptible to lethal infection after exposure to HSV-1. The importance of STING in facilitating DNA-mediated innate immune responses was further evident because cytotoxic T-cell responses induced by plasmid DNA vaccination were reduced in Sting-deficient animals. In the presence of intracellular DNA, STING relocalized with TANK-binding kinase 1 (TBK1) from the endoplasmic reticulum to perinuclear vesicles containing the exocyst component Sec5 (also known as EXOC2). Collectively, our studies indicate that STING is essential for host defence against DNA pathogens such as HSV-1 and facilitates the adjuvant activity of DNA-based vaccines.
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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 [66]
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InfluentialSelf-citationA conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1
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BackgroundResultInfluentialSTING Agonists as Cancer Therapeutics
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InfluentialSensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS
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Alterations of immune response of non-small cell lung cancer with Azacytidine
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Activation of STAT6 by STING Is Critical for Antiviral Innate Immunity
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“When the presence of cytoplasmic DNA is detected, the product of cyclic GMP-AMP synthase (cGAS), cyclic GMPAMP (cGAMP), activates STING to upregulate transcription of a type I interferon gene through a STING-TBK-IRF3-NFκB signaling pathway (Ishikawa et al., 2009; Tanaka and Chen, 2012; Li et al., 2013; Sun et al., 201…”
BackgroundCarozza, J. A., Böhnert, V., Nguyen, K. C., Skariah, G. M., Shaw, K. E., Brown, J. A., Rafat, M., von Eyben, R., Graves, E. E., Glenn, J. S., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0028-4 · Cited by 375
Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways
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Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy
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Microbial Sensing by Toll-Like Receptors and Intracellular Nucleic Acid SensorsPreprint
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“In resting cells, STING is localized in the mitochondrial-associated membrane (MAM)/ ER, but after HSV-1 infection, it rapidly traffics via unclear mechanisms to an uncharacterized perinuclear region, although this endosomal compartment containing STING and TBK1 does involve autophagy-related gene 9a (Atg9a) (Ishikawa…”
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“Previous studies clearly demonstrated that both type I IFN and STING are important for restricting HSV-1 infection in vivo (Ishikawa et al., 2009; Leib et al., 1999), and STINGmediated IFN response was assumed to be the default mechanism.”
ResultRecognition of herpesviruses by the innate immune system
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“A stimulator of interferon genes (STING) (Ishikawa and Barber, 2008; Ishikawa et al., 2009), also known as MITA (Zhong et al.”
InfluentialMutant p53 Suppresses Innate Immune Signaling to Promote Tumorigenesis
Ghosh, M., Saha, S., Bettke, J. A., Nagar, R., Parrales, A., Iwakuma, T., van der Velden, A. W. M., & Martinez, L. A. (2020) · Cancer Cell · doi:10.1016/j.ccell.2021.01.003 · Cited by 355
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“An endoplasmic reticulum (ER) resident transmembrane protein, STING (stimulator of IFNgenes, also known asMITA,ERIS, MPYS or TMEM173), was found to play essential roles for cytosolic dsDNA-mediated production of type I IFN and inflammatory cytokines through activating the TANK-binding kinase 1 (TBK1)IFN regulatory fac…”
BackgroundResultInfluentialSelf-citationIFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication
Jakobsen, M. R., Bak, R. O., Andersen, A., Berg, R. K., Jensen, S. B., Jin, T., Laustsen, A., Hansen, K., Østergaard, L., Fitzgerald, K. A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311669110 · Cited by 344
“dsDNA-induced IFN responses have been reported to proceed through a pathway involving stimulator of IFN genes (STING), TANK-binding kinase (TBK1), and IFN regulatory factor (IRF) 3 and 7 (4, 24, 27, 28).”
BackgroundExorcising the Exocyst Complex
Heider, M. R., & Munson, M. (2012) · Traffic · doi:10.1111/j.1600-0854.2012.01353.x · Cited by 344
“The exocyst also has roles in host survival responses – several studies have linked exocyst function to various aspects of the innate immune response (92,93).”
BackgroundThe AIM 2 inflammasome: Sensor of pathogens and cellular perturbations
Lugrin, J., & Martinon, F. (2018) · Immunological Reviews · doi:10.1111/imr.12618 · Cited by 333
IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes
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STING-dependent cytosolic DNA sensing pathways
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Self-citationMoretti, J., Roy, S., Bozec, D., Martinez, J., Chapman, J. R., Ueberheide, B. M., Lamming, D. W., Chen, Z. J., Horng, T., Yeretssian, G., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.034 · Cited by 341
“Upon activation, STING localizes with the vesicular transport facilitator Sec5 (Ishikawa et al., 2009), exhibits a punctate expression pattern reminiscent of autophagosomes, and gains co-localization with several autophagy proteins such as Atg9a, p62, and LC3 (Saitoh et al., 2009; Watson et al., 2012).”
InfluentialZhao, Z., Ma, Z., Wang, B., Guan, Y., Su, X., & Jiang, Z. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108053 · Cited by 334
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“The cGAS/STING pathway can sense cytosolic DNA and transduce a signal to stimulate inflammation (Ishikawa et al., 2009).”
BackgroundComprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy
Zheng, J., Mo, J., Zhu, T., Zhuo, W., Yi, Y., Hu, S., Yin, J., Zhang, W., Zhou, H., & Liu, Z. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01250-1 · Cited by 344
Interleukin-1β Induces mtDNA Release to Activate Innate Immune Signaling via cGAS-STING
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“STING signaling turns on immediately after ER exit, and it remains active throughout the trafficking process until the vesicle stage, as TBK1 can be detected to colocalize with STING as early as ERGIC and as late as post-Golgi vesicles (Dobbs et al., 2015; Ishikawa et al., 2009).”
The emerging field of oncolytic virus-based cancer immunotherapy
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Chen, R., Zou, J., Chen, J., Zhong, X. Y., Kang, R., & Tang, D. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02264-1 · Cited by 392
Prolonged activation of innate immune pathways by a polyvalent STING agonist
Li, S., Luo, M., Wang, Z., Feng, Q., Wilhelm, J., Wang, X., Li, W., Wang, J., Cholka, A., Fu, Y., et al. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-020-00675-9 · Cited by 327
Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells
Tang, C.-H. A., Zundell, J. A., Ranatunga, S., Lin, C., Nefedova, Y., Valle, J. R. D., & Hu, C. A. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-1885 · Cited by 322
“Although STING−/− mice have been shown to be incapable of mounting antibody responses after immunization with a DNA vaccine encoding ovalbumin (13), the response of B cells to STING agonists is still unknown.”
Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway
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Manganese salts function as potent adjuvants
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Induction and function of type I and III interferon in response to viral infection
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“Given its association with the translocon, it has been suggested that STING participates directly in TBK1 recruitment through physical interaction with the exocyst complex.”
BackgroundInfluentialRole of the cGAS–STING pathway in systemic and organ-specific diseases
Skopelja‐Gardner, S., An, J., & Elkon, K. B. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00589-6 · Cited by 318
Non-cell-autonomous cancer progression from chromosomal instability
Li, J., Hubisz, M. J., Earlie, E. M., Paez, M. A. D., Hong, C., Varela, A., Lettera, E., Deyell, M., Tavora, B., Havel, J. J., et al. (2023) · Nature · doi:10.1038/s41586-023-06464-z · Cited by 349
Kidney physiology and susceptibility to acute kidney injury: implications for renoprotection
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Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses
Ma, Z., Jacobs, S. R., West, J. A., Stopford, C. M., Zhang, Z., Davis, Z. H., Barber, G. N., Glaunsinger, B. A., Dittmer, D. P., & Damania, B. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1503831112 · Cited by 318
“This result is also consistent with our findings that both TBK1 and IRF3 phosphorylation was greatly attenuated when vIRF1 was present in the cells, and that this decrease in phosphorylation of TBK1 and IRF3 is similar to the effects seen in cells depleted for STING or cGAS and transfected with KSHV120.”
BackgroundInfluentialSelf-citationManganese-Based Nanoactivator Optimizes Cancer Immunotherapy via Enhancing Innate Immunity
Hou, L., Tian, C., Yan, Y., Zhang, L., Zhang, H., & Zhang, Z. (2020) · ACS Nano · doi:10.1021/acsnano.9b06111 · Cited by 313
Mechanisms and pathways of innate immune activation and regulation in health and cancer
Cui, J., Chen, Y., Wang, H. Y., & Wang, R. (2014) · Human Vaccines & Immunotherapeutics · doi:10.4161/21645515.2014.979640 · Cited by 327
“STING is a newly discovered adaptor protein, which plays a central role in viral dsDNA responses by mediating TBK1dependent IRF3 activation.(70,71) Inactive STING resides in the endoplasmic reticulum (ER), but forms discrete punctate foci with TBK1 in the perinuclear region of the cytosol after dsDNA stimulation.”
BackgroundMao, Y., Luo, W., Zhang, L., Wu, W., Yuan, L., Xu, H. Y., Song, J., Fujiwara, K., Abe, J., LeMaire, S. A., et al. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.309017 · Cited by 307
“Recent studies suggest that STING is critically involved in inflammation in response to signals of cytosolic DNA that is released from viruses or damaged nuclei or mitochondria.(25,29,30) Through cyclic GMP-AMP synthase (cGAS), cytosolic DNA can be converted to the second messenger cGAMP, which then binds to and activ…”
BackgroundWang, F., Su, H., Xu, D., Dai, W., Zhang, W., Wang, Z., Anderson, C. F., Zheng, M., Oh, R., Wan, F., et al. (2020) · Nature Biomedical Engineering · doi:10.1038/s41551-020-0597-7 · Cited by 315
Technologies for enhanced efficacy of DNA vaccines
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The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection
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“Furthermore, Listeria-induced caspase-11 expression and caspase-1 activation were impaired in macrophages deficient in STING, a critical adaptor regulating type I IFN production in response to Listeria infection (Figure 6H) (Ishikawa et al., 2009).”
Acute Pancreatitis: A Multifaceted Set of Organelle and Cellular Interactions
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Bacteria‐Based Cancer Immunotherapy
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Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice
Xie, X., Ma, G., Li, X., Zhao, J., Zhao, Z., & Zeng, J. (2023) · Nature Aging · doi:10.1038/s43587-022-00337-2 · Cited by 292
Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes
Cerboni, S., Jeremiah, N., Gentili, M., Gehrmann, U., Conrad, C., Stolzenberg, M., Pïcard, C., Neven, B., Fischer, A., Amigorena, S., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20161674 · Cited by 303
“The antiproliferative activity of STI NG required STI NG localization to the Golgi and a subdomain in the C-terminal domain, termed miniCTT, distinct from TBK1 and IRF3 recruitment domains.”
BackgroundInfluentialTight nuclear tethering of cGAS is essential for preventing autoreactivity
Volkman, H. E., Cambier, S., Gray, E. E., & Stetson, D. B. (2019) · eLife · doi:10.7554/elife.47491 · Cited by 303
“The cGAS-STING DNA sensing pathway has emerged as a key innate immune response that is important for antiviral immunity (Goubau et al., 2013), contributes to specific autoimmune diseases (Crowl et al., 2017), and mediates important aspects of antitumor immunity (Li and Chen, 2018). cGAS binds to double-stranded DNA an…”
BackgroundInfluentialSTING Recognition of Cytoplasmic DNA Instigates Cellular Defense
Abe, T., Harashima, A., Xia, T., Konno, H., Konno, K., Morales, A. A., Ahn, J., Gutman, D. M., & Barber, G. N. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.039 · Cited by 311
“We noted that ssDNA of 45 nt (ssDNA45) weakly induced innate immune gene production in hTERTBJ1s and less so in MEFs (Ishikawa and Barber, 2008; Ishikawa et al., 2009).”
InfluentialSelf-citationCancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity
Schadt, L., Sparano, C., Schweiger, N. A., Siliņa, K., Cecconi, V., Lucchiari, G., Yagita∥, H., Guggisberg, E., Saba, S., Naščáková, Z., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.065 · Cited by 299
“The Efficacy of DNA-Damaging Cancer Therapies Depends on Cancer-Cell-Intrinsic Expression of cGAS In response to DNA damage, genomic instability, or viral infection, the amount of cytoplasmic dsDNA is increased in eukaryotic cells (Fenech et al., 2011; Harding et al., 2017; Ishikawa et al., 2009; Mackenzie et al., 201…”
BackgroundLama, L., Adura, C., Xie, W., Tomita, D., Kamei, T., Kuryavyi, V., Gogakos, T., Steinberg, J. I., Miller, M., Ramos-Espiritu, L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08620-4 · Cited by 303
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“(B-F) HEK293T cells were transfected with ΔRIG-I or MITA/STING expression plasmid plus luciferase reporter plasmids for ISRE, NF-κB or IFNB1 activation.”
InfluentialThe Antiviral Innate Immune Response in Fish: Evolution and Conservation of the IFN System
Langevin, C., Aleksejeva, E., Passoni, G., Palha, N., Levraud, J., & Boudinot, P. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.09.033 · Cited by 299
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Trial watch: STING agonists in cancer therapy
Le Naour, J., Zitvogel, L., Galluzzi, L., Vacchelli, E., & Kroemer, G. (2020) · OncoImmunology · doi:10.1080/2162402x.2020.1777624 · Cited by 289
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“Barber’s group (33, 42) showing that, in vivo, MPYS was required only for early (6 hpi) but not late (12 hpi) IFN-a and -b production in response to vesicular stomatitis virus infection.”
BackgroundOlagnier, D., Brandtoft, A. M., Gunderstofte, C., Villadsen, N. L., Krapp, C., Thielke, A. L., Laustsen, A., Peri, S., Hansen, A. L., Bonefeld, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05861-7 · Cited by 282
Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response
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“Following that, the STING dimer translocates from the ER to perinuclear ER-Golgi intermediate compartment (ERGIC) vesicles, finally arriving at the Golgi to form punctuate structures with downstream molecules (2, 63).”
BackgroundCyclic di-GMP Sensing via the Innate Immune Signaling Protein STING
Yin, Q., Tian, Y., Kabaleeswaran, V., Jiang, X., Tu, D., Eck, M. J., Chen, Z. J., & Wu, H. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.029 · Cited by 293
“STING also functions as an adaptor protein in cytosolic dsDNA-induced innate immune response (Ishikawa et al., 2009) in addition to as a direct sensor of bacterial second messengers (Burdette et al., 2011).”
InfluentialThe Role of Interferons in Inflammation and Inflammasome Activation
Kopitar-Jerala, N. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00873 · Cited by 260
“Moreover, an endoplasmic reticulum-associated molecule referred to as stimulator of interferon genes (STING) was reported to control a signaling pathway important for the detection of cytosolic DNA and type I IFN expression (31, 32).”
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“Finally, our studies indicated that STING was important for intracellular DNA-mediated and HSV-1 activated type I IFN production in pDCs, although the presence of TLR9 in these cells was found to partially compensate for the loss of STING in response to Listeria infection [14].”
BackgroundInfluentialSelf-citationCasadio, M., Ciancanelli, M. J., Ou, Y.-H., Lorenzo, L., Klaudel‐Dreszler, M., Pauwels, E., Sancho‐Shimizu, V., de Diego, R. P., Abhyankar, A., Israelsson, E., et al. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20111316 · Cited by 292
“…in many antiviral pathways other than the TLR3 cascade, including the RIG-I/MDA-5 (Fitzgerald et al., 2003; Sharma et al., 2003; Hemmi et al., 2004), DAI (DLM1/ZBP1; Takaoka et al., 2007), and IFI16/STING (Ishikawa and Barber, 2008; Ishikawa et al., 2009; Unterholzner et al., 2010) pathways.”
BackgroundMolecular regulation of interferon antiviral response in fish
Zhang, Y.-B., & Gui, J. (2012) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2012.06.003 · Cited by 279
Metadata
- Authors
- Ishikawa, H., Ma, Z., & Barber, G. N.
- Affiliations
- University of Miami (US)
- Corresponding author
- Barber, Glen N.
- Venue
- Nature
- Published
- 2009-09-23
- Volume
- 461
- Issue
- 7265
- Pages
- 788-792
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4664154
- OpenAlex
- W1968178474
- Semantic Scholar
- 1098beb4c76eacfcc093a88d02d02a681585e7c4
- Cited by
- 2,759
- References
- 31
- Citations by year
- 2026: 184 · 2025: 229 · 2024: 240 · 2023: 240 · 2022: 237 · 2021: 249 · 2020: 212 · 2019: 182 · 2018: 147 · 2017: 170 · 2016: 110 · 2015: 118 · 2014: 114 · 2013: 115 · 2012: 78
- FWCI
- 30.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI079336, R56AI079336, R01AI079336)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- STING, mita, Eris, type I interferon, innate immunity, herpes simplex virus type 1, TBK1, Sec5, endosomes, DNA vaccine, plasmid DNA immunization, Listeria monocytogenes, viral susceptibility, dendritic cells
- MeSH terms
- STING Protein, Animals, Antigen-Presenting Cells, DNA, Bacterial, DNA, Viral, Endoplasmic Reticulum, Fibroblasts, Immunity, Innate, Interferon Type I, Listeria monocytogenes, Membrane Proteins, Plasmids, T-Lymphocytes, Cytotoxic, Protein Serine-Threonine Kinases, Herpesvirus 1, Human, Mice, Knockout, Vaccines, DNA, Protein Transport, Cytoplasmic Vesicles, Vesicular Transport Proteins, Intracellular Space, Mice
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