TY - JOUR
T1 - STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death
AU - Wu, Jianjun
AU - Chen, Yu Ju
AU - Dobbs, Nicole
AU - Sakai, Tomomi
AU - Liou, Jen
AU - Miner, Jonathan J.
AU - Yan, Nan
N1 - Publisher Copyright:
© 2019 Wu et al.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064143120&partnerID=8YFLogxK
U2 - 10.1084/jem.20182192
DO - 10.1084/jem.20182192
M3 - Article
C2 - 30886058
AN - SCOPUS:85064143120
SN - 0022-1007
VL - 216
SP - 867
EP - 883
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -