STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death
Open accessAbstract
STING gain-of-function mutations cause lung disease and T cell cytopenia through unknown mechanisms. Here, we found that these mutants induce chronic activation of ER stress and unfolded protein response (UPR), leading to T cell death by apoptosis in the StingN153S/+ mouse and in human T cells. Mechanistically, STING-N154S disrupts calcium homeostasis in T cells, thus intrinsically primes T cells to become hyperresponsive to T cell receptor signaling–induced ER stress and the UPR, leading to cell death. This intrinsic priming effect is mediated through a novel region of STING that we name “the UPR motif,” which is distinct from known domains required for type I IFN signaling. Pharmacological inhibition of ER stress prevented StingN153S/+ T cell death in vivo. By crossing StingN153S/+ to the OT-1 mouse, we fully restored CD8+ T cells and drastically ameliorated STING-associated lung disease. Together, our data uncover a critical IFN-independent function of STING that regulates calcium homeostasis, ER stress, and T cell survival.
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Gain-of-function STING-N153S mutation resulted in T cell deficiency.
“and gain-of-function STING-N153S mutation resulted in T cell deficiency.85”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [85]
STING activity induces T cell apoptosis.
“as recent evidence demonstrated that STING activity induces T cell apoptosis,85–87”
From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [85]
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- Bouis D., Kirstetter P., Arbogast F., Lamon D., Delgado V., Jung S., Ebel C., Jacobs H., Knapp A.-M., Jeremiah N., 2018 Severe combined immunodeficiency in Sting V154M/WT mice. J. Allergy Clin. Immunol. 143: 712– 725.e5. 10.1016/j.jaci.2018.04.034 29800647 · DOI
- Burdette D.L., Monroe K.M., Sotelo-Troha K., Iwig J.S., Eckert B., Hyodo M., Hayakawa Y., and Vance R.E. 2011 STING is a direct innate immune sensor of cyclic di-GMP. Nature. 478: 515– 518. 10.1038/nature10429 21947006 PMC3203314 · DOI · Paper page
- Cerboni S., Jeremiah N., Gentili M., Gehrmann U., Conrad C., Stolzenberg M.-C., Picard C., Neven B., Fischer A., Amigorena S., 2017 Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes. J. Exp. Med. 214: 1769– 1785. 10.1084/jem.20161674 28484079 PMC5461003 · DOI
- Chang C.-L., Chen Y.-J., Quintanilla C.G., Hsieh T.-S., and Liou J. 2018 EB1 binding restricts STIM1 translocation to ER-PM junctions and regulates store-operated Ca2+ entry. J. Cell Biol. 217: 2047– 2058. 10.1083/jcb.201711151 29563214 PMC5987725 · DOI
- Dobbs N., Burnaevskiy N., Chen D., Gonugunta V.K., Alto N.M., and Yan N. 2015 STING activation by translocation from the ER Is associated with infection and autoinflammatory disease. Cell Host Microbe. 18: 157– 168. 10.1016/j.chom.2015.07.001 26235147 PMC4537353 · DOI
- Gao D., Wu J., Wu Y.-T., Du F., Aroh C., Yan N., Sun L., and Chen Z.J. 2013 Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science. 341: 903– 906. 10.1126/science.1240933 23929945 PMC3860819 · DOI
- Gulen M.F., Koch U., Haag S.M., Schuler F., Apetoh L., Villunger A., Radtke F., and Ablasser A. 2017 Signalling strength determines proapoptotic functions of STING. Nat. Commun. 8: 427 10.1038/s41467-017-00573-w 28874664 PMC5585373 · DOI · Paper page
- Kamimura D., Katsunuma K., Arima Y., Atsumi T., Jiang J.-J., Bando H., Meng J., Sabharwal L., Stofkova A., Nishikawa N., 2015 KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR. Nat. Commun. 6: 7474 10.1038/ncomms8474 26081938 PMC4557295 · DOI
- Kieper W.C., and Jameson S.C. 1999 Homeostatic expansion and phenotypic conversion of naïve T cells in response to self peptide/MHC ligands. Proc. Natl. Acad. Sci. USA. 96: 13306– 13311. 10.1073/pnas.96.23.13306 10557316 PMC23943 · DOI
- Kim S., Koch P., Li L., Peshkin L., and Mitchison T.J. 2017 Evidence for a role of calcium in STING signaling. bioRxiv. 10.1101/145854 · DOI
- König N., Fiehn C., Wolf C., Schuster M., Cura Costa E., Tüngler V., Alvarez H.A., Chara O., Engel K., Goldbach-Mansky R., 2017 Familial chilblain lupus due to a gain-of-function mutation in STING. Ann. Rheum. Dis. 76: 468– 472. 10.1136/annrheumdis-2016-209841 27566796 · DOI
- Larkin B., Ilyukha V., Sorokin M., Buzdin A., Vannier E., and Poltorak A. 2017 Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death. J. Immunol. 199: 397– 402. 10.4049/jimmunol.1601999 28615418 PMC5525333 · DOI · Paper page
- Liou J., Kim M.L., Heo W.D., Jones J.T., Myers J.W., Ferrell J.E. Jr., and Meyer T. 2005 STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15: 1235– 1241. 10.1016/j.cub.2005.05.055 16005298 PMC3186072 · DOI
- Liu S., Cai X., Wu J., Cong Q., Chen X., Li T., Du F., Ren J., Wu Y.-T., Grishin N.V., and Chen Z.J. 2015 Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 347: aaa2630 10.1126/science.aaa2630 25636800 · DOI · Paper page
- Liu Y., Jesus A.A., Marrero B., Yang D., Ramsey S.E., Sanchez G.A.M., Tenbrock K., Wittkowski H., Jones O.Y., Kuehn H.S., 2014 Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371: 507– 518. 10.1056/NEJMoa1312625 25029335 PMC4174543 · DOI
- Margolis S.R., Wilson S.C., and Vance R.E. 2017 Evolutionary Origins of cGAS-STING Signaling. Trends Immunol. 38: 733– 743. 10.1016/j.it.2017.03.004 28416447 · DOI
- Melki I., Rose Y., Uggenti C., Van Eyck L., Frémond M.-L., Kitabayashi N., Rice G.I., Jenkinson E.M., Boulai A., Jeremiah N., 2017 Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling. J. Allergy Clin. Immunol. 140: 543– 552.e5. 10.1016/j.jaci.2016.10.031 28087229 · DOI
- Pino S.C., O’Sullivan-Murphy B., Lidstone E.A., Thornley T.B., Jurczyk A., Urano F., Greiner D.L., Mordes J.P., Rossini A.A., and Bortell R. 2008 Protein kinase C signaling during T cell activation induces the endoplasmic reticulum stress response. Cell Stress Chaperones. 13: 421– 434. 10.1007/s12192-008-0038-0 18418732 PMC2673927 · DOI
- Pokatayev V., Hasin N., Chon H., Cerritelli S.M., Sakhuja K., Ward J.M., Morris H.D., Yan N., and Crouch R.J. 2016 RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J. Exp. Med. 213: 329– 336. 10.1084/jem.20151464 26880576 PMC4813680 · DOI · Paper page
- Prakriya M., and Lewis R.S. 2015 Store-operated calcium channels. Physiol. Rev. 95: 1383– 1436. 10.1152/physrev.00020.2014 26400989 PMC4600950 · DOI
- Srikanth S., Woo J.S., Wu B., El-Sherbiny Y.M., Leung J., Chupradit K., Rice L., Seo G.J., Calmettes G., Ramakrishna C., 2019 The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat. Immunol. 20: 152– 162. 10.1038/s41590-018-0287-8 30643259 PMC6340781 · DOI
- Sun L., Wu J., Du F., Chen X., and Chen Z.J. 2013 Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 339: 786– 791. 10.1126/science.1232458 23258413 PMC3863629 · DOI · Paper page
- Warner J.D., Irizarry-Caro R.A., Bennion B.G., Ai T.L., Smith A.M., Miner C.A., Sakai T., Gonugunta V.K., Wu J., Platt D.J., 2017 STING-associated vasculopathy develops independently of IRF3 in mice. J. Exp. Med. 214: 3279– 3292. 10.1084/jem.20171351 28951494 PMC5679177 · DOI
- Wu J., Sun L., Chen X., Du F., Shi H., Chen C., and Chen Z.J. 2013 Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science. 339: 826– 830. 10.1126/science.1229963 23258412 PMC3855410 · DOI
- Wu J.-J., Li W., Shao Y., Avey D., Fu B., Gillen J., Hand T., Ma S., Liu X., Miley W., 2015 Inhibition of cGAS DNA sensing by a herpesvirus virion protein. Cell Host Microbe. 18: 333– 344. 10.1016/j.chom.2015.07.015 26320998 PMC4567405 · DOI
- Yan N. 2017 Immune diseases associated with TREX1 and STING dysfunction. J. Interferon Cytokine Res. 37: 198– 206. 10.1089/jir.2016.0086 28475463 PMC5439420 · DOI
- Yan N., Regalado-Magdos A.D., Stiggelbout B., Lee-Kirsch M.A., and Lieberman J. 2010 The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11: 1005– 1013. 10.1038/ni.1941 20871604 PMC2958248 · DOI
- Yang H., Wang H., Ren J., Chen Q., and Chen Z.J. 2017 cGAS is essential for cellular senescence. Proc. Natl. Acad. Sci. USA. 114: E4612– E4620. 10.1073/pnas.1705499114 28533362 PMC5468617 · DOI · Paper page
- Zhang J., Feng H., Zhao J., Feldman E.R., Chen S.-Y., Yuan W., Huang C., Akbari O., Tibbetts S.A., and Feng P. 2016 IκB kinase ε is an NFATc1 kinase that inhibits T cell immune response. Cell Reports. 16: 405– 418. 10.1016/j.celrep.2016.05.083 27346349 PMC5293007 · DOI
- Zhang X., Shi H., Wu J., Zhang X., Sun L., Chen C., and Chen Z.J. 2013 Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell. 51: 226– 235. 10.1016/j.molcel.2013.05.022 23747010 PMC3808999 · DOI
- Authors
- Wu, J., Chen, Y.-J., Dobbs, N., Sakai, T., Liou, J., Miner, J. J., & Yan, N.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Washington University in St. Louis (US)
- Corresponding author
- Yan, Nan
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2019-03-18
- Volume
- 216
- Issue
- 4
- Pages
- 867-883
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6446864
- OpenAlex
- W2924757324
- Cited by
- 323
- References
- 32
- Citations by year
- 2026: 40 · 2025: 55 · 2024: 62 · 2023: 49 · 2022: 55 · 2021: 33 · 2020: 19 · 2019: 10
- FWCI
- 15.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (AR067135, AI134877, GM113079, AR070918)
- Cancer Prevention and Research Institute of Texas (RP180288)
- Burroughs Wellcome Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- STING, calcium homeostasis, endoplasmic reticulum stress, unfolded protein response, T cell apoptosis, T cell survival, CD8+ T cells, T cell receptor signaling
- MeSH terms
- Gain of Function Mutation, STING Protein, Animals, Calcium, Disease Models, Animal, Homeostasis, Humans, Lung Diseases, Lymphocyte Activation, Membrane Proteins, Mice, Transgenic, Transfection, Apoptosis, CD8-Positive T-Lymphocytes, Mice, Unfolded Protein Response, HEK293 Cells, Endoplasmic Reticulum Stress
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