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 A. Marsh (3) , Carolina Uggenti (3) , Gillian I. Rice (4) , Vincent Bondet (5) , Darragh Duffy (5) , Jonny Hertzog (6) , Jan Rehwinkel (6) , Serge Amselem (7, 8, 9) , Siham Boulisfane-El Khalifi (10) , Mary Brennan (11) , Edwin Carter (3) , Lucienne Chatenoud (12) , Stéphanie Chhun (12) , Aurore Coulomb L'Hermine (13, 14) , Marine Depp (3) , Marie Legendre (7, 8, 9) , Karen J. Mackenzie (3) , Jonathan Marey (15) , Catherine Mcdougall (11) , Kathryn J. Mckenzie (16) , Thierry Jo Molina (17) , Bénédicte Neven (18, 1) , Luis Seabra (1) , Caroline Thumerelle (10) , Marie Wislez (15, 19) , Nadia Nathan (7, 8, 20) , 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 Inserm U933 - Maladies génétiques d'expression pédiatrique [CHU Trousseau]
8 CHU Trousseau [APHP]
9 UF de Génétique moléculaire [CHU Trousseau]
10 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
11 Royal Hospital for Sick Children [Edinburgh]
12 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
13 Service de pathologie [CHU Trousseau]
14 SU - Sorbonne Université
15 Service de pneumologie [CHU Cochin]
16 Royal Infirmary of Edinburgh
17 Département de Pathologie [CHU Necker]
18 Service d'immuno-hématologie pédiatrique [CHU Necker]
19 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
20 Service de Pneumologie pédiatrique [CHU Trousseau]

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.

Domains: Life Sciences [q-bio]; Immunology

Alice Lepelley, Maria José Martin-Niclos, Melvin Le Bihan, Joseph A. Marsh, Carolina Uggenti, et al.. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling. Journal of Experimental Medicine, 2020, 217 (11), pp.e20200600. ⟨10.1084/jem.20200600⟩. ⟨pasteur-02933253⟩