STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death

DOI PDF 被引用文献2件
  • Jianjun Wu
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 1
  • Yu-Ju Chen
    Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 3
  • Nicole Dobbs
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 1
  • Tomomi Sakai
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 1
  • Jen Liou
    Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 3
  • Jonathan J. Miner
    Department of Medicine, Washington University School of Medicine, St. Louis, MO 4
  • Nan Yan
    Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 1

書誌事項

公開日
2019-03-18
権利情報
  • http://www.rupress.org/terms/
  • https://creativecommons.org/licenses/by-nc-sa/4.0/
DOI
  • 10.1084/jem.20182192
公開者
Rockefeller University Press

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説明

<jats:p>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.</jats:p>

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