STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death
Year: 2019
Type: article
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.
DOI: 10.1084/jem.20182192
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: Functions and regulation of endoplasmic reticulum-plasma membrane junctions, Innate Immune Regulation of Cancer Cell Proliferation, A DNase-Independent Function of TREX1/DNase III in Systemic Lupus Erythematosus, STING Trafficking, Activation and Signaling Beyond Interferon, Contributions of IRF5 to Chikungunya Viral Arthritis, Mechanisms of STING-associated autoinflammation
OpenAlex ID: W2924757324