| First Author | Wu J | Year | 2019 |
| Journal | J Exp Med | Volume | 216 |
| Issue | 4 | Pages | 867-883 |
| PubMed ID | 30886058 | Mgi Jnum | J:273012 |
| Mgi Id | MGI:6286644 | Doi | 10.1084/jem.20182192 |
| Citation | Wu J, et al. (2019) STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death. J Exp Med 216(4):867-883 |
| abstractText | 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 vivo. By crossing Sting(N153S/+) 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. |
