A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome

Abstract

Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling1,2. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport3. Missense mutations that disrupt the COPA WD40 domain impair binding and sorting of proteins targeted for retrieval to the ER but how this causes disease remains unknown1,4. 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. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addtion, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.