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 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.

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

“…Stimulator of interferon genes activation on the ER also triggers an ER stress response with an "unfolded protein response (UPR) motif " on the C-terminus of STING, which leads to and ER stress-mediated autophagy (82,83). STING-TBK1 activation and ER stress also induce mechanistic target of rapamycin complex 1 (mTORC1) dysfunction (84).…”

“…Localization of STING at the Golgi can cause delay of T-cell mitosis and reduced proliferation independently of IRF3 and TBK1 (215). Furthermore, a "UPR motif " on the C-terminus of STING can cause ER stress and UPR, resulting in Ca 2+ overloading and T-cell death (82). A controversial view is that B cells express STING variously and may undergo apoptosis through this way (166,216,217).…”

cGAS/STING: novel perspectives of the classic pathway

“…Besides, STING activates ER stress and the unfolded protein response (UPR) through a novel motif termed as "the UPR motif", which is located in the helix aa322-343. Long-lasting STINGmediated ER stress and disruption of calcium homeostasis primes T cell death by apoptosis [132][133][134] (Fig.6e).…”

Dexmedetomidine versus ketamine in attenuating neuropathic pain through modulating STING/TBK pathway to modulate spinal ER-phagy in neuropathic pain model

“…In this study, our data indicated that STING/TBK pathway was activated in the spinal cord of neuropathic pain model. Activated STING signaling triggers ER stress (48). STING-containing endoplasmic reticulum-Golgi intermediate compartment (ERGIC) served as a membrane source for the lipidation of LC3 (20,49,50).…”