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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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Self-citationSTING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway
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“…proteomics that the CD8+ DC subpopulation selectively lacks the receptors and signaling molecules (such as DAI [Takaoka et al., 2007] and Sting [Ishikawa et al., 2009]) required for the detection of nucleotides in the cytoplasm (Luber et al., 2010), so if this is indeed the pathway involved in…”
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“Bax/Bak double-KO and control immortalized MEFs were provided by Dr. C. Thompson (University of Pennsylvania) (Wei et al., 2001), and primary STING KO (Tmem173 / ) MEFs were provided by Dr. G. Barber (University of Miami) (Ishikawa et al., 2009).”
MethodGoubau, D., Deddouche, S., & Sousa, C. R. E. (2013) · Immunity · doi:10.1016/j.immuni.2013.05.007 · Cited by 875
“After dsDNA stimulation, STING rapidly traffics from the ER through the Golgi into perinuclear punctate structures that also contain the kinase TBK1 (Ishikawa et al., 2009; Saitoh et al., 2009; Tanaka and Chen, 2012).”
BackgroundInfluentialStructures and Mechanisms in the cGAS-STING Innate Immunity Pathway
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Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response
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“An endoplasmic-reticulum-resident host protein called stimulator of IFN genes (STING; also called TMEM173, MITA, ERIS, and MPYS) was shown to be required for IFN response to cytosolic dsDNA (Ishikawa and Barber, 2008; Ishikawa et al., 2009; Sun et al., 2009; Zhong et al., 2008).”
BackgroundExosomes maintain cellular homeostasis by excreting harmful DNA from cells
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“The endoplasmic reticulum (ER) membrane-localized adaptor protein STING is essential for the responses to cytosolic DNA (Barber, 2011b; Ishikawa and Barber, 2008; Ishikawa et al., 2009; Sun et al., 2009; Zhong et al., 2009).”
BackgroundCell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP
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“’’ To then confirm previous results (Ishikawa et al., 2009) that BFA inhibits STING signaling in our model system, we treated MEFs with increasing doses of BFA or nocodazole for 1 hr and transfected DNA to activate STING signaling and IFN expression.”
InfluentialPost-Translational Modification Control of Innate Immunity
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“For the TRIF-dependent pathway, TRIF activates TRAF3/TANK-binding kinase 1 (TBK1) axis to promote phosphorylation of IRF3, which induces the expression of type I IFN.”
BackgroundInfluentialMarcus, A., Mao, A. J., Lensink-Vasan, M., Wang, L., Vance, R. E., & Raulet, D. H. (2018) · Immunity · doi:10.1016/j.immuni.2018.09.016 · Cited by 609
“cGAMP binds and activates the endoplasmic reticulum (ER)-resident adaptor protein STING (stimulator of interferon genes protein) (Ablasser et al., 2013a; Diner et al., 2013; Gao et al., 2013c; Ishikawa et al., 2009; Zhang et al., 2013), which leads to the downstream activation of the transcription factors IFN regulato…”
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“Tumors with defective STING-Signaling are sensitive to viral Oncolysis We have previously shown that loss of STING signaling in vitro or in vivo renders cells or mice, respectively, extremely sensitive to Herpes simplex virus (HSV) infection (Ishikawa and Barber, 2008; Ishikawa et al., 2009).”
BackgroundMethodInfluentialSelf-citationDiscriminating self from non-self in nucleic acid sensing
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Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury
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Nucleic acid recognition by the innate immune system
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STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity
Demaria, O., Gassart, A. D., Coso, S., Gestermann, N., Domizio, J. D., Flatz, L., Gaide, O., Michielin, O. A., Hwu, P., Petrova, T. V., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1512832112 · Cited by 585
“Because STING has been associated with type I IFN induction (21) we next sought to investigate the role of type I IFNs in mediating the antitumor CD8 T-cell response induced by cGAMP.”
BackgroundYum, S., Li, M., Fang, Y., & Chen, Z. J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2100225118 · Cited by 596
“STING-deficient mice are susceptible to HSV-1 infection whereas wild-type (WT) mice survive and clear the virus within a few days (20).”
BackgroundIRF3 and type I interferons fuel a fatal response to myocardial infarction
King, K. R., Aguirre, A. D., Ye, Y., Sun, Y., Roh, J. D., Ng, R. P., Köhler, R. H., Arlauckas, S. P., Iwamoto, Y., Savol, A. J., et al. (2017) · Nature Medicine · doi:10.1038/nm.4428 · Cited by 583
Quantitative proteomics reveals subset-specific viral recognition in dendritic cells
Luber, C. A., Cox, J., Lauterbach, H., Fancke, B., Selbach, M., Tschopp, J., Akira, S., Wiegand, M., Hochrein, H., O'Keeffe, M., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.01.013 · Cited by 576
Jin, T., Perry, A., Jiang, J., Smith, P. T., Curry, J. A., Unterholzner, L., Jiang, Z., Horvath, G. L., Rathinam, V. A. K., Johnstone, R. W., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.02.014 · Cited by 608
“The cytosolic signaling pathway for interferon induction downstream of IFI16 appears to require the ER resident protein STING (stimulator of interferon genes) (Ishikawa et al., 2009; Unterholzner et al., 2010), which itself was shown to be a nucleotide sensor that induces type I IFN production (Burdette et al.”
Decoding type I and III interferon signalling during viral infection
Mesev, E. V., LeDesma, R. A., & Ploss, A. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0421-x · Cited by 538
Jeremiah, N., Neven, B., Gentili, M., Callebaut, I., Maschalidi, S., Stolzenberg, M.-C., Goudin, N., Frémond, M.-L., Nitschke, P., Molina, T. J., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci79100 · Cited by 562
“Activation of STING is known to induce type I IFN production through TBK-1 phosphorylation and IRF3 phosphorylation (9).”
Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic
Chin, E. N., Yu, C., Vartabedian, V. F., Jia, Y., Kumar, M. N. S., Gamo, A. M., Vernier, W. F., Ali, S. H., Kissai, M., Lazar, D. C., et al. (2020) · Science · doi:10.1126/science.abb4255 · Cited by 560
Ubiquitin chain diversity at a glance
Akutsu, M., Đikić, I., & Bremm, A. (2016) · Journal of Cell Science · doi:10.1242/jcs.183954 · Cited by 594
“Microbial DNA triggers STING dimerization and its migration from the ER to the perinuclear microsome compartment (Ishikawa et al., 2009).”
BackgroundTumor Microenvironment as A “Game Changer” in Cancer Radiotherapy
Jarosz–Biej, M., Smolarczyk, R., Cichoń, T., & Kułach, N. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133212 · Cited by 549
“IR also induces the production of IFN (type I) by activating a stimulator of interferon genes (STING) pathway in tumor-infiltrating DCs, as well as the increased secretion of CXCL10, a C-X-C chemokine receptor (CXCR3+) that recruits IFN-γ secreting CD8+ T cells [34,75].”
BackgroundSauer, J., Troha, K., von Moltke, J., Monroe, K. M., Rae, C. S., Brubaker, S. W., Hyodo, M., Hayakawa, Y., Woodward, J. J., Portnoy, D. A., et al. (2010) · Infection and Immunity · doi:10.1128/iai.00999-10 · Cited by 528
“In addition, as reported previously for Sting / cells (9), Sting cells responded normally to transfection of poly(I:C) (Fig.”
BackgroundDNA released from dying host cells mediates aluminum adjuvant activity
Marichal, T., Ohata, K., Bedoret, D., Mesnil, C., Sabatel, C. M., Kobiyama, K., Lekeux, P. M., Coban, C., Akira, S., Ishii, K. J., et al. (2011) · Nature Medicine · doi:10.1038/nm.2403 · Cited by 538
Cyclic GMP–AMP signalling protects bacteria against viral infection
Cohen, D., Melamed, S., Millman, A., Shulman, G., Oppenheimer-Shaanan, Y., Kacen, A., Doron, S., Amitai, G., & Sorek, R. (2019) · Nature · doi:10.1038/s41586-019-1605-5 · Cited by 535
Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee‐Kirsch, M. A., & Lieberman, J. (2010) · Nature Immunology · doi:10.1038/ni.1941 · Cited by 522
Linking cellular stress responses to systemic homeostasis
Galluzzi, L., Yamazaki, T., & Kroemer, G. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0068-0 · Cited by 551
DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING
Aguirre, S., Maestre, A. M., Pagni, S. E., Patel, J. R., Savage, T. J., Gutman, D. M., Maringer, K., Bernal‐Rubio, D., Shabman, R. S., Simon, V. R., et al. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002934 · Cited by 548
Self-citationPestal, K., Funk, C. C., Snyder, J. M., Price, N. D., Treuting, P. M., & Stetson, D. B. (2015) · Immunity · doi:10.1016/j.immuni.2015.11.001 · Cited by 514
“129S4Meox2 cross were subsequently bred to Tmem173 / (Sting / ) mice (Ishikawa et al., 2009), Mavs / mice (Gall et al.”
BackgroundProgrammed cell death and the immune system
Nagata, S., & Tanaka, M. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2016.153 · Cited by 540
STING manifests self DNA-dependent inflammatory disease
Ahn, J., Gutman, D. M., Saijo, S., & Barber, G. N. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215006109 · Cited by 523
“However, we have shown that Stimulator of IFNGenes (STING), an endoplasmic reticulum (ER)-associated transmembrane molecule and part of the translocon complex, is a key component in controlling cytoplasmicDNA innate immune signaling and is responsible for facilitating host–defense events that comprises the production…”
BackgroundSelf-citationIFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV
Monroe, K. M., Yang, Z., Johnson, J. R., Geng, X., Doitsh, G., Krogan, N. J., & Greene, W. C. (2014) · Science · doi:10.1126/science.1243640 · Cited by 511
Gall, A., Treuting, P., Elkon, K. B., Loo, Y.-M., Gale, M., Barber, G. N., & Stetson, D. B. (2012) · Immunity · doi:10.1016/j.immuni.2011.11.018 · Cited by 510
“One pathway, called the interferon-stimulatory DNA (ISD) response (Stetson and Medzhitov, 2006a), is activated by natural DNA containing all four bases and triggers type I interferon production through the adaptor protein STING (Ishikawa et al., 2009).”
InfluentialSelf-citationSignalling strength determines proapoptotic functions of STING
Gulen, M. F., Koch, U., Haag, S. M., Schuler, F., Apetoh, L., Villunger, A., Radtke, F., & Ablasser, A. (2017) · Nature Communications · doi:10.1038/s41467-017-00573-w · Cited by 505
STING and the innate immune response to nucleic acids in the cytosol
Burdette, D. L., & Vance, R. E. (2013) · Nature Immunology · doi:10.1038/ni.2491 · Cited by 501
The Ubiquitin Ligase TRIM56 Regulates Innate Immune Responses to Intracellular Double-Stranded DNA
Tsuchida, T., Zou, J. P., Saitoh, T., Kumar, H., Abe, T., Matsuura, Y., Kawai, T., & Akira, S. (2010) · Immunity · doi:10.1016/j.immuni.2010.10.013 · Cited by 500
“…addition, STING-deficient mice show a remarkable reduction in cytotoxic T cell responses after plasmid DNA mmunity 33, 765–776, November 24, 2010 ª2010 Elsevier Inc. 765 vaccination (Ishikawa et al., 2009), indicating that STING is an essential component of dsDNA-mediated immune responses in vivo.”
BackgroundInfluentialTBK1 and IKKε Act Redundantly to Mediate STING-Induced NF-κB Responses in Myeloid Cells
Balka, K. R., Louis, C., Saunders, T. L., Smith, A. M., Calleja, D. J., D’Silva, D. B., Moghaddas, F., Tailler, M., Lawlor, K. E., Zhan, Y., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.056 · Cited by 504
“, tumor necrosis factor [TNF], IL-1b, and IL-6) through the activity of NF-kB (Ishikawa and Barber, 2008; Ishikawa et al., 2009).”
Horner, S. M., Liu, H. M., Park, H. S., Briley, J. D., & Gale, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1110133108 · Cited by 505
“STING, a putative RIG-I signaling cofactor and IPS-1 binding protein, also may have MAM localization, but this localization is likely specific to cell type and context (30).”
BackgroundPrabakaran, T., Bodda, C., Krapp, C., Zhang, B., Christensen, M. H., Sun, C., Reinert, L. S., Cai, Y., Jensen, S. B., Skouboe, M. K., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201797858 · Cited by 488
“The induction of type I IFNs by DNA is essential for defense against virus infections and for anti-cancer immunity (Ishikawa et al , 2009; Li et al , 2013; Schoggins et al , 2013; Deng et al , 2014; Woo et al , 2014; Reinert et al , 2016).”
Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis
Jones, J. W. M., Kayagaki, N., Brož, P., Henry, T., Newton, K., O’Rourke, K. M., Chan, S. B., Dong, J. J., Qu, Y., Roose-Girma, M., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003738107 · Cited by 487
“asc, caspase-1, ifnar, nlrc4, nlrp3, and sting mice have been described (9, 23, 25, 39).”
BackgroundGehrke, N., Mertens, C., Zillinger, T., Wenzel, J., Bald, T., Zahn, S., Tüting, T., Hartmann, G., & Barchet, W. (2013) · Immunity · doi:10.1016/j.immuni.2013.08.004 · Cited by 485
“…type I interferon (IFN) by activating the endoplasmic reticulum protein STING (also known as MITA, MPYS, or ERIS [Ishikawa and Barber, 2008; Ishikawa et al., 2009; Jin et al., 2008; Sun et al., 2009; Zhong et al., 2008]) and then Tank-binding kinase 1 (TBK1) (Ishii et al., 2006; Stetson…”
BackgroundInfluentialManzanillo, P. S., Shiloh, M. U., Portnoy, D. A., & Cox, J. S. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.03.007 · Cited by 467
“BMDMs were obtained from the following mouse strains:MYD88 / /TRIF / (Barbalat et al., 2009); TREX1 / (Stetson et al., 2008); STING / (Ishikawa et al., 2009); TNFR1 / and TBK1 / /TNFR1 / (Ishii et al., 2008); and IFNAR1 / , IRF1 / , IRF3 / , IRF5 / , and IRF7 / (Takaoka et al., 2007).”
BackgroundInfluentialHIV-1 evades innate immune recognition through specific cofactor recruitment
Rasaiyaah, J., Tan, C. P., Fletcher, A. J., Price, A. J., Blondeau, C., Hilditch, L., Jacques, D. A., Selwood, D. L., James, L. C., Noursadeghi, M., et al. (2013) · Nature · doi:10.1038/nature12769 · Cited by 474
Newly described pattern recognition receptors team up against intracellular pathogens
Brož, P., & Monack, D. M. (2013) · Nature reviews. Immunology · doi:10.1038/nri3479 · Cited by 481
Viral evasion of intracellular DNA and RNA sensing
Chan, Y., & Gack, M. U. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.45 · Cited by 458
Negishi, H., Taniguchi, T., & Yanai, H. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a028423 · Cited by 447
“The induction of dsDNA-mediated type I IFN gene expression is markedly impaired in STING/MITA-deficient cells (Zhong et al. 2008; Ishikawa et al. 2009).”
Background
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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