CoChat
Sign Up
Cited by 505interferon and immune responsesImmune Response and InflammationImmunotherapy and Immune Responses

Signalling strength determines proapoptotic functions of STING

Open access
Gulen, Muhammet F., Koch, Ute, Haag, Simone M., Schuler, Fabian, Apetoh, Lionel, Villunger, Andreas, Radtke, Freddy, Ablasser, Andrea·2017·Nature Communications
DOI 10.1038/s41467-017-00573-wPMC PMC5585373
Open this paper in CoChat — free accountOpen PDF

Abstract

Mammalian cells use cytosolic nucleic acid receptors to detect pathogens and other stress signals. In innate immune cells the presence of cytosolic DNA is sensed by the cGAS–STING signalling pathway, which initiates a gene expression programme linked to cellular activation and cytokine production. Whether the outcome of the STING response varies between distinct cell types remains largely unknown. Here we show that T cells exhibit an intensified STING response, which leads to the expression of a distinct set of genes and results in the induction of apoptosis. Of note, this proapoptotic STING response is still functional in cancerous T cells and delivery of small molecule STING agonists prevents in vivo growth of T-cell-derived tumours independent of its adjuvant activity. Our results demonstrate how the magnitude of STING signalling can shape distinct effector responses, which may permit for cell type-adjusted behaviours towards endogenous or exogenous insults.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-017-00573-w

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 30

  1. [1]Wu J Chen ZJ Innate immune sensing and signaling of cytosolic nucleic acids Annu. Rev. Immunol. 2014 32 461 488 10.1146/annurev-immunol-032713-120156 24655297 · DOI
  2. [2]Sun L Wu J Du F Chen X Chen ZJ Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway Science 2013 339 786 791 10.1126/science.1232458 23258413 PMC3863629 · DOI · Paper page
  3. [3]Wu J Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA Science 2013 339 826 830 10.1126/science.1229963 23258412 PMC3855410 · DOI
  4. [5]Ablasser A cGAS produces a 2ʹ-5ʹ-linked cyclic dinucleotide second messenger that activates STING Nature 2013 498 380 384 10.1038/nature12306 23722158 PMC4143541 · DOI · Paper page
  5. [6]Diner EJ The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING Cell Rep. 2013 3 1355 1361 10.1016/j.celrep.2013.05.009 23707065 PMC3706192 · DOI · Paper page
  6. [7]Liu S Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation Science 2015 347 aaa2630 10.1126/science.aaa2630 25636800 · DOI · Paper page
  7. [8]Woo SR STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors Immunity 2014 41 830 842 10.1016/j.immuni.2014.10.017 25517615 PMC4384884 · DOI · Paper page
  8. [9]Konno H Konno K Barber GN Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling Cell 2013 155 688 698 10.1016/j.cell.2013.09.049 24119841 PMC3881181 · DOI
  9. [10]Petrasek J STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease Proc. Natl Acad. Sci. USA 2013 110 16544 16549 10.1073/pnas.1308331110 24052526 PMC3799324 · DOI
  10. [11]Sze A Host restriction factor SAMHD1 limits human T cell leukemia virus type 1 infection of monocytes via STING-mediated apoptosis Cell Host. Microbe. 2013 14 422 434 10.1016/j.chom.2013.09.009 24139400 · DOI
  11. [12]Tang CH Agonist-mediated activation of STING induces apoptosis in malignant B cells Cancer Res. 2016 76 2137 2152 10.1158/0008-5472.CAN-15-1885 26951929 PMC4873432 · DOI
  12. [13]Sauer JD The N-ethyl-N-nitrosourea-induced goldenticket mouse mutant reveals an essential function of sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides Infect. Immun. 2011 79 688 694 10.1128/IAI.00999-10 21098106 PMC3028833 · DOI
  13. [14]Cavlar T Deimling T Ablasser A Hopfner KP Hornung V Species-specific detection of the antiviral small-molecule compound CMA by STING EMBO J. 2013 32 1440 1450 10.1038/emboj.2013.86 23604073 PMC3655471 · DOI
  14. [15]Marsden VS Strasser A Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more Annu. Rev. Immunol. 2003 21 71 105 10.1146/annurev.immunol.21.120601.141029 12414721 · DOI
  15. [16]Liu Y Activated STING in a vascular and pulmonary syndrome N. Engl. J. Med. 2014 371 507 518 10.1056/NEJMoa1312625 25029335 PMC4174543 · DOI
  16. [18]Wendorff AA Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation Immunity 2010 33 671 684 10.1016/j.immuni.2010.11.014 21093323 · DOI
  17. [19]Burdette DL STING is a direct innate immune sensor of cyclic di-GMP Nature 2011 478 515 518 10.1038/nature10429 21947006 PMC3203314 · DOI · Paper page
  18. [20]Bridgeman A Viruses transfer the antiviral second messenger cGAMP between cells Science 2015 349 1228 1232 10.1126/science.aab3632 26229117 PMC4617605 · DOI
  19. [21]Gentili M Transmission of innate immune signaling by packaging of cGAMP in viral particles Science 2015 349 1232 1236 10.1126/science.aab3628 26229115 · DOI
  20. [22]Barber GN STING: infection, inflammation and cancer Nat. Rev. Immunol. 2015 15 760 770 10.1038/nri3921 26603901 PMC5004891 · DOI · Paper page
  21. [23]Ablasser A Gulen MF The role of cGAS in innate immunity and beyond J. Mol. Med. 2016 94 1085 1093 10.1007/s00109-016-1423-2 27154323 · DOI
  22. [25]McWhirter SM A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP J. Exp. Med. 2009 206 1899 1911 10.1084/jem.20082874 19652017 PMC2737161 · DOI
  23. [26]Corrales L Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity Cell Rep. 2015 11 1018 1030 10.1016/j.celrep.2015.04.031 25959818 PMC4440852 · DOI · Paper page
  24. [27]Demaria O STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity Proc. Natl Acad. Sci. USA 2015 112 15408 15413 10.1073/pnas.1512832112 26607445 PMC4687570 · DOI
  25. [28]Gao D Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses Science 2013 341 903 906 10.1126/science.1240933 23929945 PMC3860819 · DOI
  26. [29]Lahaye X The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells Immunity 2013 39 1132 1142 10.1016/j.immuni.2013.11.002 24269171 · DOI · Paper page
  27. [30]Hemmi H The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection J. Exp. Med. 2004 199 1641 1650 10.1084/jem.20040520 15210742 PMC2212809 · DOI
  28. [31]Wassermann R Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1 Cell. Host. Microbe 2015 17 799 810 10.1016/j.chom.2015.05.003 26048138 · DOI · Paper page
  29. [32]Ablasser A Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP Nature 2013 503 530 534 10.1038/nature12640 24077100 PMC4142317 · DOI
  30. [33]Barde, I., Salmon, P. & Trono, D. Production and titration of lentiviral vectors. Curr. Protoc. Neurosci. doi: 10.1002/0471142301.ns0421s53 (2010). 20938923 · DOI

Cited by

Sorted by citations

Authors
Gulen, M. F., Koch, U., Haag, S. M., Schuler, F., Apetoh, L., Villunger, A., Radtke, F., & Ablasser, A.
Affiliations
  • École Polytechnique Fédérale de Lausanne (CH)
  • Innsbruck Medical University (AT)
Corresponding author
Ablasser, Andrea
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-09-05
Volume
8
Issue
1
Pages
427-427
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-00573-w
PMC
PMC5585373
OpenAlex
W2750976328
Cited by
505
References
3
Citations by year
2026: 42 · 2025: 76 · 2024: 70 · 2023: 63 · 2022: 78 · 2021: 60 · 2020: 47 · 2019: 40 · 2018: 27 · 2017: 1
FWCI
14.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Funders
  • Novartis Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (2014_A250, 159836, 155984)
  • Austrian Science Fund (FOR-2036, I1298)
  • Else Kröner-Fresenius-Stiftung (31003A_159836, 2014_A250)
  • Novartis Stiftung für Medizinisch-Biologische Forschung
  • H2020 European Research Council (677251)
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, cGAS-STING pathway, cytosolic DNA sensing, T cells, apoptosis, STING agonist, innate immunity, cancer immunotherapy, T-cell leukemia
MeSH terms
STING Protein, Animals, Membrane Proteins, Mice, Inbred C57BL, Protein Binding, T-Lymphocytes, Transcription, Genetic, Signal Transduction, Leukemia, T-Cell, Tumor Suppressor Protein p53, Apoptosis, Interferon Regulatory Factor-3

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review