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

ABSTRACT: 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

SUBMITTER: Wu J 

PROVIDER: S-EPMC6446864 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature