PT  - JOURNAL ARTICLE
AU  - Zimu Deng
AU  - Zhenlu Chong
AU  - Christopher S. Law
AU  - Kojiro Mukai
AU  - Frances O. Ho
AU  - Tereza Martinu
AU  - Bradley J. Backes
AU  - Walter L. Eckalbar
AU  - Tomohiko Taguchi
AU  - Anthony K. Shum
TI  - A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome
AID  - 10.1101/2020.05.20.106500
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.20.106500
4099  - http://biorxiv.org/content/early/2020/05/20/2020.05.20.106500.short
4100  - http://biorxiv.org/content/early/2020/05/20/2020.05.20.106500.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.