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

Jianjun Wu, Yu Ju Chen, Nicole Dobbs, Tomomi Sakai, Jen Liou, Jonathan J. Miner, Nan Yan

Research output: Contribution to journalArticlepeer-review

127 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)867-883
Number of pages17
JournalJournal of Experimental Medicine
Issue number4
StatePublished - Apr 1 2019

ASJC Scopus subject areas

  • Medicine(all)


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