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Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling

Alice Lepelley 1 Maria José Martin-Niclos 1 Melvin Le Bihan 2 Joseph Marsh 3 Carolina Uggenti 3 Gillian Rice 4 Vincent Bondet 5 Darragh Duffy 5 Jonny Hertzog 6 Jan Rehwinkel 6 Serge Amselem 7, 8 Siham Boulisfane-El Khalifi 9 Mary Brennan 10 Edwin Carter 3 Lucienne Chatenoud 11 Stéphanie Chhun 11 Aurore Coulomb l'Hermine 12, 13 Marine Depp 3 Marie Legendre 7, 8 Karen Mackenzie 3 Jonathan Marey 14 Catherine Mcdougall 10 Kathryn Mckenzie 15 Thierry Jo Molina 16 Bénédicte Neven 17, 1 Luis Seabra 1 Caroline Thumerelle 9 Marie Wislez 14, 18 Nadia Nathan 7, 8 Nicolas Manel 2 Yanick Crow 1, 3 Marie-Louise Frémond 1
1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 U932 - Immunité et cancer
3 IGMM - MRC Institute of Genetics and Molecular Medicine [Edinburgh]
4 MAHSC - Manchester Academic Health Science Centre
5 Immunobiologie des Cellules dendritiques
6 Radcliffe Department of Medicine [Oxford]
7 Physiopathologie des maladies génétiques d'expression pédiatrique
8 CHU Trousseau [APHP]
9 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
10 Royal Hospital for Sick Children [Edinburgh]
11 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
12 Service de pathologie [CHU Trousseau]
13 SU - Sorbonne Université
14 Service de pneumologie [CHU Cochin]
15 Royal Infirmary of Edinburgh
16 Département de Pathologie [CHU Necker]
17 Service d'immuno-hématologie pédiatrique [CHU Necker]
18 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
Abstract : Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
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Alice Lepelley, Maria José Martin-Niclos, Melvin Le Bihan, Joseph Marsh, Carolina Uggenti, et al.. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling. Journal of Experimental Medicine, Rockefeller University Press, 2020, 217 (11), pp.e20200600. ⟨10.1084/jem.20200600⟩. ⟨pasteur-02933253⟩

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