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STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death
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 Sting(N153S/+) mouse and in human T cells. Me...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446864/ https://www.ncbi.nlm.nih.gov/pubmed/30886058 http://dx.doi.org/10.1084/jem.20182192 |
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author | Wu, Jianjun Chen, Yu-Ju Dobbs, Nicole Sakai, Tomomi Liou, Jen Miner, Jonathan J. Yan, Nan |
author_facet | Wu, Jianjun Chen, Yu-Ju Dobbs, Nicole Sakai, Tomomi Liou, Jen Miner, Jonathan J. Yan, Nan |
author_sort | Wu, Jianjun |
collection | PubMed |
description | 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 Sting(N153S/+) 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 Sting(N153S/+) T cell death in vivo. By crossing Sting(N153S/+) 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. |
format | Online Article Text |
id | pubmed-6446864 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-64468642019-10-01 STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death Wu, Jianjun Chen, Yu-Ju Dobbs, Nicole Sakai, Tomomi Liou, Jen Miner, Jonathan J. Yan, Nan J Exp Med Research Articles 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 Sting(N153S/+) 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 Sting(N153S/+) T cell death in vivo. By crossing Sting(N153S/+) 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. Rockefeller University Press 2019-04-01 2019-03-18 /pmc/articles/PMC6446864/ /pubmed/30886058 http://dx.doi.org/10.1084/jem.20182192 Text en © 2019 Wu et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Wu, Jianjun Chen, Yu-Ju Dobbs, Nicole Sakai, Tomomi Liou, Jen Miner, Jonathan J. Yan, Nan STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death |
title | STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death |
title_full | STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death |
title_fullStr | STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death |
title_full_unstemmed | STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death |
title_short | STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death |
title_sort | sting-mediated disruption of calcium homeostasis chronically activates er stress and primes t cell death |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446864/ https://www.ncbi.nlm.nih.gov/pubmed/30886058 http://dx.doi.org/10.1084/jem.20182192 |
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