Cited by 2,759interferon and immune responsesImmune Response and InflammationImmunotherapy and Immune Responses

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STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

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Ishikawa, Hiroki, Ma, Zhe, Barber, Glen N.·2009·Nature

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Abstract

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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The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses
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Ishikawa, H., & Barber, G. N. (2008) · Nature · doi:10.1038/nature07317 · Cited by 3,576
Self-citation
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A distinct role of STING in regulating glucose homeostasis through insulin sensitivity and insulin secretion
Qiao, J., Zhang, Z., Ji, S., Liu, T., Zhang, X., Huang, Y., Feng, W., Wang, K., Wang, J., Wang, S., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2101848119 · Cited by 78
UNC93B1 attenuates the cGAS–STING signaling pathway by targeting STING for autophagy–lysosome degradation
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“that STING trafficking from ER to Golgi is required to activate and recruit TBK1 and IKK complex and produce type I interferon (IFN‐I) and proinflammatory cytokines, respectively.(1,2,11) The cGAS–STING axis plays a critical role in modeling the host antiviral defense against viral invasion.”
Background
Listeria monocytogenes Multidrug Resistance Transporters and Cyclic Di-AMP, Which Contribute to Type I Interferon Induction, Play a Role in Cell Wall Stress
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TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer
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“Recombinant active TBK1 (14-628) and BX795 (204001) were from EMD Millipore.”
BackgroundMethod
STING-Licensed Macrophages Prime Type I IFN Production by Plasmacytoid Dendritic Cells in the Bone Marrow during Severe Plasmodium yoelii Malaria
Spaulding, E., Fooksman, D., Moore, J. M. R., Saidi, A., Feintuch, C. M., Reizis, B., Chorro, L., Daily, J. P., & Lauvau, G. S. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005975 · Cited by 76
Radiotherapy: An immune response modifier for immuno-oncology
Martino, M. D., Daviaud, C., & Vanpouille‐Box, C. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101474 · Cited by 81
Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)
David, C., & Frémond, M. (2022) · Cells · doi:10.3390/cells11030318 · Cited by 81
The Common R71H-G230A-R293Q Human TMEM173 Is a Null Allele
Patel, S., Blaauboer, S. M., Tucker, H. R., Mansouri, S., Ruiz-Moreno, J. S., Hamann, L., Schumann, R. R., Opitz, B., & Jin, L. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1601585 · Cited by 73
“DNA viruses (7), RNA viruses (7, 8), intracellular bacteria (9, 10), and extracellular bacteria (11, 12) in mice.”
Background
Efficacy and mechanism of cGAMP to suppress Alzheimer’s disease by elevating TREM2
Xu, Q., Xu, W., Cheng, H., Yuan, H., & Tan, X. (2019) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2019.07.004 · Cited by 75
Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response
Bayyurt, B., Almacioglu, K., Alpdundar, E., Akpinar, G. G., Tincer, G., Bayık, D., Gürsel, M., & Gürsel, İ. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.09.040 · Cited by 75
Local scaffold-assisted delivery of immunotherapeutic agents for improved cancer immunotherapy
Shang, Q., Dong, Y., Su, Y., Leslie, F., Sun, M., & Wang, F. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114308 · Cited by 74
Regulation of cGAS and STING signaling during inflammation and infection
Chauvin, S. D., Stinson, W. A., Platt, D. J., Poddar, S., & Miner, J. J. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104866 · Cited by 77
“monocytogenes, Chlamydia trachomatis, and Salmonella enterica (93, 137, 139), in the cecal ligation and puncture model of sepsis, loss of STING is protective against death and bacteremia (140–142).”
BackgroundInfluential
Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway
Cheng, L., Zhang, P., Liu, Y., Liu, Z., Tang, J., Xu, L., & Liu, J. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122259 · Cited by 79
Nanovaccines: An effective therapeutic approach for cancer therapy
Gurunathan, S., Pratheep, T., Wang, L., Cao, Q., & Kim, J. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115992 · Cited by 78
Nucleic acid driven sterile inflammation
Ablasser, A., Hertrich, C., Wassermann, R., & Hornung, V. (2013) · Clinical Immunology · doi:10.1016/j.clim.2013.01.003 · Cited by 79
Posttranslational Modification as a Critical Determinant of Cytoplasmic Innate Immune Recognition
Baker, P. J., Nardo, D. D., Moghaddas, F., Tran, L. S., Bachem, A., Nguyen, T. A., Hayman, T. J., Tye, H., Vince, J. E., Bedoui, S., et al. (2017) · Physiological Reviews · doi:10.1152/physrev.00026.2016 · Cited by 75
“In the absence of STING, mice are highly susceptible to virusinduced lethality due to a lack of IFN-I production (136, 137).”
Background
STING Signaling in Cancer Cells: Important or Not?
Sokołowska, O., & Nowis, D. (2017) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-017-0481-7 · Cited by 79
“After phosphorylation IRF3 translocates to the nucleus and triggers transcription of IFNB1 and several other genes, which promote expression of proinflammatory cytokines, such as interleukin 6 and tumor necrosis factor a (Ishikawa et al. 2009; Woo et al. 2014).”
BackgroundInfluential
Epstein–Barr Virus and Innate Immunity: Friends or Foes?
Jangra, S., Yuen, K., Botelho, M. G., & Jin, D. (2019) · Microorganisms · doi:10.3390/microorganisms7060183 · Cited by 74
Triggering of the cGAS-STING Pathway in Human Plasmacytoid Dendritic Cells Inhibits TLR9-Mediated IFN Production
Deb, P., Dai, J., Singh, S., Kalyoussef, E., & Fitzgerald-Bocarsly, P. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1800933 · Cited by 72
“cleus and inducing type I IFN production (13, 14).”
BackgroundInfluential
Interfering with immunity: detrimental role of type I IFNs during infection
Stifter, S. A., & Feng, C. G. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402794 · Cited by 78
Danger signals: Chemotherapy enhancers?
Vargas, T. R., & Apétoh, L. (2017) · Immunological Reviews · doi:10.1111/imr.12581 · Cited by 73
The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13
Mulas, F., Wang, X., Song, S., Nishanth, G., Yi, W., Brunn, A., Larsen, P., Isermann, B., Kalinke, U., Barragán, A., et al. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0362-6 · Cited by 74
Enhancement of the viability of T cells electroporated with DNA via osmotic dampening of the DNA-sensing cGAS–STING pathway
An, J., Chuan-ping, Z., Qiu, H.-Y., Zhang, H., Chen, Q., Zhang, Y., Lei, X., Zhang, C., Yin, H., & Zhang, Y. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-023-01073-7 · Cited by 79
“One hallmark of STING activation is the temporal upregulation of type-I interferon (IFN) gene expression and the apoptosis marker Noxa 15,19,24,25 .”
cGAS–STING, an important signaling pathway in diseases and their therapy
Li, Q., Wu, P., Du, Q., Hanif, U., Hu, H., & Li, K. (2024) · MedComm · doi:10.1002/mco2.511 · Cited by 83
A Type I Photosensitizer-Polymersome Boosts Reactive Oxygen Species Generation by Forcing H-Aggregation for Amplifying STING Immunotherapy
Wang, Z., Ma, W., Yáng, Z., Kiesewetter, D. O., Wu, Y., Lang, L., Zhang, G., Nakuchima, S., Chen, J., Su, Y. P., et al. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c09831 · Cited by 74
Transcriptome response to heat stress in a chicken hepatocellular carcinoma cell line
Sun, L., Lamont, S. J., Cooksey, A. M., McCarthy, F., Tudor, C. O., Vijay‐Shanker, K., DeRita, R. M., Rothschild, M. F., Ashwell, C. M., Persia, M. E., et al. (2015) · Cell Stress and Chaperones · doi:10.1007/s12192-015-0621-0 · Cited by 75
“1999), transmembrane protein 173 (TMEM173) responds to viral infection (Ishikawa et al. 2009), and regulatory factor X (RFX2) is involved in testes development (Horvath et al.”
Background
A role for DNA-dependent activator of interferon regulatory factor in the recognition of herpes simplex virus type 1 by glial cells
Furr, S. R., Chauhan, V. S., Moerdyk-Schauwecker, M. J., & Marriott, I. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-99 · Cited by 75
“Finally, to begin to determine whether DAI is functional in glial cells we have investigated whether these cells express RIP3 and STING, two critical downstream effector molecules in DAI signaling [29-31].”
Background
AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA
Nakaya, Y., Lilue, J., Stavrou, S., Moran, E. A., & Ross, S. R. (2017) · mBio · doi:10.1128/mbio.00944-17 · Cited by 75
“STING, in turn, activates tank-binding kinase 1 (TBK1) and transcription factor IFN regulatory factor 3 (IRF3), thereby inducing the expression of type I IFN, as well as other cytokines (18).”
RIG-I is required for VSV-induced cytokine production by murine glia and acts in combination with DAI to initiate responses to HSV-1
Crill, E. K., Furr, S. R., & Marriott, I. (2015) · Glia · doi:10.1002/glia.22883 · Cited by 73
“In support of this possibility, immunoprecipitation studies indicate that STING associates with RIG-I complexes in close proximity to endoplasmic reticulum associated-mitochondria (Dixit et al., 2010; Ishikawa et al., 2009).”
Background
miR-H28 and miR-H29 expressed late in productive infection are exported and restrict HSV-1 replication and spread in recipient cells
Han, Z., Liu, X., Chen, X., Zhou, X., Du, T., Roizman, B., & Zhou, G. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525674113 · Cited by 72
“One hypothesis to explain the data is that HSV has evolved functions that depend on host defense mechanisms to control viral replication and spread. ii) STING (stimulator of interferon genes) is an important component of the signaling cascade that leads to the activation of IFN (23, 24).”
Background
In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP–AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing
Zhao, W., Xiong, M., Yuan, X., Li, M., Sun, H., & Xu, Y. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00171 · Cited by 72
Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection
Shen, Q., Wang, Y. E., & Palazzo, A. F. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100856 · Cited by 71
Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma
Low, J., Brown, M. C., Reitman, Z. J., Bernstock, J. D., Markert, J. M., Friedman, G. K., Waitkus, M. S., Bowie, M. L., & Ashley, D. M. (2024) · Journal of Clinical Investigation · doi:10.1172/jci163452 · Cited by 81
MPYS/STING-Mediated TNF-α, Not Type I IFN, Is Essential for the Mucosal Adjuvant Activity of (3′–5′)-Cyclic-Di-Guanosine-Monophosphate In Vivo
Blaauboer, S. M., Gabrielle, V. D., & Jin, L. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301812 · Cited by 72
“A previous report (21) showed that STING is also required for the adjuvant activity of DNA.”
Background
Ubiquitin-mediated modulation of the cytoplasmic viral RNA sensor RIG-I
Oshiumi, H., Matsumoto, M., & Seya, T. (2011) · The Journal of Biochemistry · doi:10.1093/jb/mvr111 · Cited by 72
“However, RIG-I polyubiquitination is essential for NF-kB activation by RIG-I, which is required for IL-1b mRNA expression; thus, knockout of TRIM25 reduces the production of mature IL-1b (4, 19, 27).”
BackgroundInfluential
Type I Interferon Induction by Neisseria gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4
Andrade, W. A., Agarwal, S., Mo, S., Shaffer, S. A., Dillard, J. P., Schmidt, T., Hornung, V., Fitzgerald, K. A., Kurt‐Jones, E. A., & Golenbock, D. T. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.030 · Cited by 77
“…host protein called stimulator of IFN genes (STING) is required for a type I IFN response to cytosolic double-stranded DNA (dsDNA) (Ishikawa et al., 2009), and IFN responses to a family of unique bacterial nucleic acids that form cyclic dinucleotides (Sauer et al., 2011).”
Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response
Gries, C. M., Bruger, E. L., Moormeier, D. E., Scherr, T. D., Waters, C. M., & Kielian, T. (2016) · Infection and Immunity · doi:10.1128/iai.00447-16 · Cited by 74
UBXN3B positively regulates STING-mediated antiviral immune responses
Yang, L., Wang, L., Ketkar, H., Ma, J., Yang, G., Cui, S., Geng, T., Mordue, D. G., Fujimoto, T., Cheng, G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04759-8 · Cited by 73
Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer
Durand, J. K., Zhang, Q. H., & Baldwin, A. S. (2018) · Cells · doi:10.3390/cells7090139 · Cited by 73
“Interestingly, RalB/Sec5 are involved in the innate response and TBK1 activation [77,78].”
Background
STAT3 inhibition enhances CDN-induced STING signaling and antitumor immunity
Pei, J., Zhang, Y., Luo, Q., Zheng, W., Li, W., Zeng, X. Y., Li, Q., & Quan, J. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.02.029 · Cited by 74
Telltale tumor infiltrating lymphocytes (TIL) in oral, head & neck cancer
Lei, Y. L., Xie, Y., Tan, Y. S., Prince, M. E., Moyer, J. S., Nor, J. E., & Wolf, G. T. (2016) · Oral Oncology · doi:10.1016/j.oraloncology.2016.08.003 · Cited by 76
“This second messenger activates the adaptor protein Stimulator of Interferon Genes (STING) to trigger IFN-I signaling (Figure 1) [56, 57].”
Background
Innate Immune Mechanisms and Herpes Simplex Virus Infection and Disease
Kurt‐Jones, E. A., Orzalli, M. H., & Knipe, D. M. (2017) · Advances in anatomy, embryology and cell biology · doi:10.1007/978-3-319-53168-7_3 · Cited by 71
“…to HSV-1 and fail to mount a type I IFN response suggesting that cGAS activation of STING is the major driver of IFN response in animals (Ishikawa et al. 2009; Schoggins et al. 2015; Li et al. 2013; Parker et al. 2015; Royer and Carr 2016). cGAS knockouts rapidly succumb to HSV-1 with…”
Background
Hepatocellular Carcinoma Growth Retardation and PD-1 Blockade Therapy Potentiation with Synthetic High-density Lipoprotein
Wang, J., Meng, J., Wei, R., Lee, R. J., Teng, L., Zhang, P., & Li, Y. (2019) · Nano Letters · doi:10.1021/acs.nanolett.9b01717 · Cited by 72
Subversion of Host Innate Immunity by Human Papillomavirus Oncoproteins
Cigno, I. L., Calati, F., Albertini, S., & Gariglio, M. (2020) · Pathogens · doi:10.3390/pathogens9040292 · Cited by 73
Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections
Acosta, P. L., Byrne, A. B., Hijano, D. R., & Talarico, L. B. (2020) · Journal of Immunology Research · doi:10.1155/2020/1372494 · Cited by 75
“YFV NS4B interacts with STING, blocking IFN-I stimulation [253].”
cGAS/STING cross-talks with cell cycle and potentiates cancer immunotherapy
Long, Z., Wang, J., Xu, J., Lei, X., & Liu, Q. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.01.044 · Cited by 76
“Subsequently, as the major effectors of innate immunity, interferon regulatory factor 3 (IRF3) and nuclear factor kB (NF-kB) are activated to induce the production of type I interferons (IFNs) and other cytokines, triggering immune responses (Figure 2).(5,39,40)”
Background
STING controls energy stress-induced autophagy and energy metabolism via STX17
Rong, Y., Zhang, S., Nandi, N., Wu, Z., Li, L., Liu, Y., Wei, Y., Zhao, Y., Yuan, W., Zhou, C., et al. (2022) · The Journal of Cell Biology · doi:10.1083/jcb.202202060 · Cited by 74
“…promote the dimerization and translocation of STING from the ER, in a sequential manner, to ERGIC, Golgi, and finally to endolysosomes (Burdette et al., 2011; Chu et al., 2021; Dobbs et al., 2015; Ishikawa et al., 2009; Saitoh et al., 2009; Sun et al., 2013; Woodward et al., 2010; Wu et al., 2013).”
Development of LB244, an Irreversible STING Antagonist
Barasa, L., Chaudhuri, S., Zhou, J. Y., Jiang, Z., Choudhary, S., Green, R. M., Wiggin, E., Cameron, M. D., Humphries, F., Fitzgerald, K. A., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c03637 · Cited by 72
Using Plasmids as DNA Vaccines for Infectious Diseases
Tregoning, J. S., & Kinnear, E. (2014) · Microbiology Spectrum · doi:10.1128/microbiolspec.plas-0028-2014 · Cited by 72
“Studies have shown that the downstream signaling molecules STING and TBK1 are essential for instigation of an innate immune response to DNA vaccines, as their deletion abrogated type I interferon production (50, 51).”
Background
The Emerging Role of Nuclear Viral DNA Sensors
Diner, B. A., Lum, K. K., & Cristea, I. M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.652289 · Cited by 74
“Furthermore, Sting / mice more readily succumb to HSV-1 infection and fail to generate appropriate adaptive immune responses to DNA vaccines (21).”
Background
The role of mitochondria in the mammalian antiviral defense system
Scott, I. (2010) · Mitochondrion · doi:10.1016/j.mito.2010.02.005 · Cited by 71
“…press); and it has been shown further that STING/MITA is involved in the response to intracellular viral DNA produced by herpes simplex-1 virus, where it translocates from the endoplasmic reticulum (with the signaling kinase TBK-1) to perinuclear vesicles during infection (Ishikawa et al., 2009).”
Background
Innate antiviral signalling in the central nervous system
Carty, M., Reinert, L. S., Paludan, S. R., & Bowie, A. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.10.012 · Cited by 73
Hepatitis C Virus NS4B Can Suppress STING Accumulation To Evade Innate Immune Responses
Yi, G., Wen, Y., Shu, C., Han, Q., Konan, K. V., Li, P., & Kao, C. C. (2015) · Journal of Virology · doi:10.1128/jvi.01720-15 · Cited by 74
“Since STING can bind MAVS, TBK1, and IRF3, the downstream molecules of the RNA sensors RIG-I and MDA5 (45, 51, 53), it is possible that STING triggers the innate immune response through cross talk with RNA sensors.”
Background
CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections
Sung, P., & Hsieh, S.-L. E. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02867 · Cited by 71
“IFN genes), MPYS (methionine-proline-tyrosineserine), MITA (mediator of IRF3 activation), or ERIS (ER IFN stimulator) (12, 13).”
Background
Golgi Apparatus: An Emerging Platform for Innate Immunity
Tao, Y., Yang, Y., Zhou, R., & Gong, T. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.02.008 · Cited by 71
Conserved strategies for pathogen evasion of cGAS–STING immunity
Eaglesham, J. B., & Kranzusch, P. J. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.04.002 · Cited by 75
EGFR‐mediated tyrosine phosphorylation of STING determines its trafficking route and cellular innate immunity functions
Wang, C., Wang, X., Veleeparambil, M., Kessler, P., Willard, B. B., Chattopadhyay, S., & Sen, G. C. (2020) · The EMBO Journal · doi:10.15252/embj.2019104106 · Cited by 71
“Physiologically, STING provides protection against many bacterial and viral infections by triggering the synthesis of IFN and other cytokines and autophagy (Ishikawa et al , 2009).”
Mitochondrial Damage-Associated Molecular Patterns and Metabolism in the Regulation of Innate Immunity
Lyu, Y., Wang, T., Huang, S., & Zhang, Z. (2023) · Journal of Innate Immunity · doi:10.1159/000533602 · Cited by 76
“If mtDNA is released from the mitochondria or exits the cell, it has the potential to be internalized by PRRs located in the cytoplasm or on the cell surface, subsequently triggering in ﬂ ammatory mechanisms associated with DAMPs or immune cell activation [11 – 13].”
Background
Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis
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“All bar graphs shown as mea n ±SEM. activates cGAS and leads to the production of cyclic GMP – AMP (cGAMP), a second messenger molecule and potent agonist of STING 90 – 96 .”
Background
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The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans
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Pulmonary inflammatory and fibrogenic response induced by graphitized multi-walled carbon nanotube involved in cGAS-STING signaling pathway
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“…DNA damage, oncosuppressor gene mutations or deletions and expression of endogenous retroviruses in cancer cells can cause accumulation of cytoplasmic DNA in antigen-presenting cells and tumor cells, leading to induction of STING activation and promotion of immune-mediated clearance 114–118 .”
In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies
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DHX15 Senses Double-Stranded RNA in Myeloid Dendritic Cells
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Binding of the Duck Tembusu Virus Protease to STING Is Mediated by NS2B and Is Crucial for STING Cleavage and for Impaired Induction of IFN-β
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Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity
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Dynamic regulation of innate immunity by ubiquitin and ubiquitin-like proteins
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“STING deficient cells and mice show severely impaired interferon production in response to either DNA viruses or RNA viruses [85].”
Background
DNA vaccines against cancer come of age
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“protein, was also identified as an intracellular DNA sensor that mediates the induction of IFN-b in which stimulator of IFN genes (STING), a critical mediator (21), was recruited to IFI16 after DNA stimulation (22).”
Background
Membrane-core nanoparticles for cancer nanomedicine
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“It is now known that the stimulator of interferon genes (STING) critically regulates intracellular DNA-triggered interferon-dependent innate immunity [149].”
Background
DEAD/H-box helicases:Anti-viral and pro-viral roles during infections
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An innate antiviral pathway acting before interferons at epithelial surfaces
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A novel transcript isoform of STING that sequesters cGAMP and dominantly inhibits innate nucleic acid sensing
Wang, P., Fung, S., Gao, W., Deng, J., Cheng, Y., Chaudhary, V., Yuen, K., Ho, T., Chan, C.-P., Zhang, Y., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky186 · Cited by 70
“Activation of STING- by TBK1 results in aggregation (12,43).”
BackgroundResult
Activation of Stimulation of Interferon Genes (STING) Signal and Cancer Immunotherapy
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The ubiquitin E3 ligase TRIM10 promotes STING aggregation and activation in the Golgi apparatus
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Self-Assembled STING-Activating Coordination Nanoparticles for Cancer Immunotherapy and Vaccine Applications
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“Recent studies have shown that stimulator of interferon genes, STING (also named MPYS, MITA, or ERIS), plays a central role in the signaling cascades of cytosolic DNA sensing [13,14].”
BackgroundInfluential
Sensing Adenovirus Infection: Activation of Interferon Regulatory Factor 3 in RAW 264.7 Cells
Stein, S. C., & Falck-Pedersen, E. (2012) · Journal of Virology · doi:10.1128/jvi.07071-11 · Cited by 67
“Several studies have indicated that STING operates as a critical adaptor bridging DNA sensing cascades to a TBK1-dependent type I IFN response (17, 18, 43, 48).”
Background
Dengue viruses cleave STING in humans but not in nonhuman primates, their presumed natural reservoir
Stabell, A. C., Meyerson, N. R., Gullberg, R. C., Gilchrist, A. R., Webb, K. J., Old, W. M., Perera, R. M., & Sawyer, S. L. (2018) · eLife · doi:10.7554/elife.31919 · Cited by 70
“STING is a multi-pass transmembrane protein found in the endoplasmic reticulum, and functions as a critical component in the innate immune sensing pathway for intracellular pathogens (Ishikawa and Barber, 2008; Zhong et al., 2008; Ishikawa et al., 2009; Jin et al., 2008; Sun et al., 2009; Burdette and Vance, 2013) .”
Background
DDX41 Recognizes RNA/DNA Retroviral Reverse Transcripts and Is Critical for In Vivo Control of Murine Leukemia Virus Infection
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T Cell Co-stimulation and Functional Modulation by Innate Signals
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Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells
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STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity
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ER Adaptor SCAP Translocates and Recruits IRF3 to Perinuclear Microsome Induced by Cytosolic Microbial DNAs
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“of DNA in the cytoplasm, which has functions hostile to the virus in normal cells and in mice that impede virus replication and dissemination [99–101].”
Plasmacytoid pre-dendritic cells (pDC): from molecular pathways to function and disease association
Alculumbre, S. G., Raieli, S., Hoffmann, C., Chelbi, R., Danlos, F., & Soumelis, V. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.02.014 · Cited by 70
TANK-Binding Kinase 1-Dependent Responses in Health and Autoimmunity
Louis, C., Burns, C. J., & Wicks, I. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00434 · Cited by 64
“Ishikawa and colleagues subsequently demonstrated that intracellular DNA induced DC activation and IFN-Is production through the cGAS-STING-TBK1 pathway (67).”
Background
Causes and consequences of genomic instability in laminopathies: Replication stress and interferon response
Graziano, S., Kreienkamp, R., Coll-Bonfill, N., & Gonzalo, S. (2018) · Nucleus · doi:10.1080/19491034.2018.1454168 · Cited by 64
Self-DNA Sensing in Lung Inflammatory Diseases
Benmerzoug, S., Ryffel, B., Togbe, D., & Quesniaux, V. F. J. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.06.001 · Cited by 65
“However, cGAMP requires the endoplasmic reticulum protein STING to trigger the type I IFN pathways in human and murine cells [30, 31] (Figure 1).”
Background
Intracellular Nucleic Acid Sensors and Autoimmunity
Theofilopoulos, A. N., Kono, D. H., Beutler, B., & Baccalà, R. (2011) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2011.0092 · Cited by 66
Exocyst subunit Exo70B2 is linked to immune signaling and autophagy
Brillada, C., Teh, O.-K., Ditengou, F. A., Lee, C.-W., Klecker, T., Saeed, B., Furlan, G., Zietz, M., Hause, G., Eschen‐Lippold, L., et al. (2020) · The Plant Cell · doi:10.1093/plcell/koaa022 · Cited by 63
The Complexity of the cGAS-STING Pathway in CNS Pathologies
Fryer, A. L., Abdullah, A. D. I., Taylor, J. M., & Crack, P. J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.621501 · Cited by 65
“…by the invading pathogen and bind to pattern recognition receptors (PRRs) including toll-like receptors (TLR) and cyclic GMP-AMP synthase (cGAS) on the surface of resident immune cells such as microglia and astrocytes in the CNS (Bowman et al., 2003; Olson and Miller, 2004; Jack et al., 2005).”
Background
ICA69 aggravates ferroptosis causing septic cardiac dysfunction via STING trafficking
Kong, C., Ni, X.-Q., Wang, Y., Zhang, A., Zhang, Y., Lin, F., Li, S., Lv, Y., Zhu, J., Yao, X., et al. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-00957-y · Cited by 65
TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies
Cunniff, E. C., Sato, Y., Mai, D., Appleman, V. A., Iwasaki, S., Kolev, V. N., Matsuda, A., Shi, J. Q., Mochizuki, M., Yoshikawa, M., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-21-0161 · Cited by 64

Authors: Ishikawa, H., Ma, Z., & Barber, G. N.
Affiliations: University of Miami (US)
Corresponding author: Barber, Glen N.
ORCID: Ishikawa, Hiroki
Ma, Zhe
Barber, Glen N.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2009-09-23
Volume: 461
Issue: 7265
Pages: 788-792
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature08476
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: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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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STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

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