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

J Exp Med. 2019 Apr 1;216(4):867-883. doi: 10.1084/jem.20182192. Epub 2019 Mar 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Calcium / metabolism*
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / genetics*
  • Gain of Function Mutation
  • HEK293 Cells
  • Homeostasis / genetics*
  • Humans
  • Lung Diseases / metabolism
  • Lymphocyte Activation / genetics
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Transfection
  • Unfolded Protein Response / genetics


  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Calcium