Copa mutation activates STING and perturbs thymocyte development by increasing type I interferons in the thymus.
Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. Given the importance of COPA in Golgi-ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. Here we show that a defect in COPI transport due to mutant COPA causes ligand-independent activation of STING. Activated STING stimulates type I interferon driven inflammation in CopaE241K/+ mice. Our results demonstrate that activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease. Overall design: Differential gene expression analysis in medullary thymic epithelial cells of CopaE241K/+ mice