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, 8)
,
Siham Boulisfane-El Khalifi
(9)
,
Mary Brennan
(10)
,
Edwin Carter
(3)
,
Lucienne Chatenoud
(11)
,
Stéphanie Chhun
(11)
,
Aurore Coulomb L'Hermine
(8, 12)
,
Marine Depp
(3)
,
Marie Legendre
(7, 8, 8)
,
Karen J. Mackenzie
(3)
,
Jonathan Marey
(13)
,
Catherine Mcdougall
(10)
,
Kathryn J. Mckenzie
(14)
,
Thierry Jo Molina
(15)
,
Bénédicte Neven
(16, 1)
,
Luis Seabra
(1)
,
Caroline Thumerelle
(9)
,
Marie Wislez
(13, 17)
,
Nadia Nathan
(7, 8, 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 U933 - 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 SU - Sorbonne Université
13 Service de pneumologie [CHU Cochin]
14 Royal Infirmary of Edinburgh
15 Département de Pathologie [CHU Necker]
16 Service d'immuno-hématologie pédiatrique [CHU Necker]
17 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
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 U933 - 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 SU - Sorbonne Université
13 Service de pneumologie [CHU Cochin]
14 Royal Infirmary of Edinburgh
15 Département de Pathologie [CHU Necker]
16 Service d'immuno-hématologie pédiatrique [CHU Necker]
17 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
Alice Lepelley
- Function : Author
- PersonId : 762742
- ORCID : 0000-0001-8656-7291
Vincent Bondet
- Function : Author
- PersonId : 746608
- IdHAL : vincent-bondet
- ORCID : 0000-0002-6534-0984
Darragh Duffy
- Function : Author
- PersonId : 746816
- IdHAL : darragh-duffy
- ORCID : 0000-0002-8875-2308
- IdRef : 201316919
Jonny Hertzog
- Function : Author
- PersonId : 802349
- ORCID : 0000-0002-7089-982X
Serge Amselem
- Function : Author
- PersonId : 936326
- IdHAL : serge-amselem
- ORCID : 0000-0001-9506-3968
- IdRef : 066957761
Marie Legendre
- Function : Author
- PersonId : 1147534
- IdHAL : marie-legendre
- ORCID : 0000-0003-2178-0846
Marie Wislez
- Function : Author
- PersonId : 989590
Nicolas Manel
- Function : Author
- PersonId : 759207
- ORCID : 0000-0002-1481-4430
- IdRef : 095062467
Yanick Crow
- Function : Author
- PersonId : 11918
- IdHAL : yanick-crow
- ORCID : 0000-0001-7211-7564
- IdRef : 227205359
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.
Domains
Immunology
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