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

Autor:	Deng Z; Department of Medicine, University of California, San Francisco, San Francisco, CA., Chong Z; Department of Medicine, University of California, San Francisco, San Francisco, CA., Law CS; Department of Medicine, University of California, San Francisco, San Francisco, CA., Mukai K; Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan., Ho FO; Department of Medicine, University of California, San Francisco, San Francisco, CA., Martinu T; Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada., Backes BJ; Department of Medicine, University of California, San Francisco, San Francisco, CA., Eckalbar WL; Department of Medicine, University of California, San Francisco, San Francisco, CA., Taguchi T; Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan., Shum AK; Department of Medicine, University of California, San Francisco, San Francisco, CA.; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2020 Nov 02; Vol. 217 (11).
DOI:	10.1084/jem.20201045
Abstrakt:	Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi-ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport 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 addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease. Competing Interests: Disclosures: T. Martinu reported grants from Sanofi and non-financial support from APCBio outside the submitted work. No other disclosures were reported. (© 2020 Deng et al.)
Databáze:	MEDLINE
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