Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling-Reference-Cited by-同舟云学术

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

Published:2020-07-28 Issue:11 Volume:217 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Lepelley Alice¹^ORCID,Martin-Niclós Maria José¹^ORCID,Le Bihan Melvin²^ORCID,Marsh Joseph A.³^ORCID,Uggenti Carolina⁴^ORCID,Rice Gillian I.⁵^ORCID,Bondet Vincent⁶⁷^ORCID,Duffy Darragh⁶⁷^ORCID,Hertzog Jonny⁸^ORCID,Rehwinkel Jan⁸^ORCID,Amselem Serge⁹¹⁰^ORCID,Boulisfane-El Khalifi Siham¹¹^ORCID,Brennan Mary¹²^ORCID,Carter Edwin⁴^ORCID,Chatenoud Lucienne¹³¹⁴¹⁵^ORCID,Chhun Stéphanie¹³¹⁴¹⁵^ORCID,Coulomb l’Hermine Aurore¹⁶^ORCID,Depp Marine⁴^ORCID,Legendre Marie⁹¹⁰^ORCID,Mackenzie Karen J.³^ORCID,Marey Jonathan¹⁷^ORCID,McDougall Catherine¹⁸^ORCID,McKenzie Kathryn J.¹⁹^ORCID,Molina Thierry Jo¹³²⁰^ORCID,Neven Bénédicte¹³²¹²²^ORCID,Seabra Luis¹^ORCID,Thumerelle Caroline²³^ORCID,Wislez Marie¹⁷²⁴^ORCID,Nathan Nadia⁹²⁵^ORCID,Manel Nicolas²^ORCID,Crow Yanick J.¹⁴^ORCID,Frémond Marie-Louise¹^ORCID

Affiliation:

1. Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Paris, France

2. Immunity and Cancer Department, Institut Curie, Paris-Sciences-et-Lettres Research University, Institut National de la Santé et de la Recherche Médicale U932, Paris, France

3. Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK

4. Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK

5. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

6. Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France

7. Institut National de la Santé et de la Recherche Médicale U1223, Paris, France

8. Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

9. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale/UMRS_933, Trousseau University Hospital, Paris, France

10. Genetics Department, Trousseau University Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France

11. Emergency, Infectious Disease and Pediatric Rheumatology Department, Centre Hospitalier Régional Universitaire Lille, University of Lille, Lille, France

12. Department of Paediatric Rheumatology, Royal Hospital for Sick Children, Edinburgh, UK

13. Paris Descartes University, Université de Paris, Sorbonne-Paris-Cité, Paris, France

14. Laboratory of Immunology, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France

15. Institut Necker-Enfants Malades, Centre National de la Recherche Scientifique UMR8253, Institut National de la Santé et de la Recherche Médicale UMR1151, Team Immunoregulation and Immunopathology, Paris, France

16. Pathology Department, Trousseau University Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France

17. Pneumology Department, Cochin Hospital, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France

18. Department of Paediatric Respiratory Medicine, Royal Hospital for Sick Children, Edinburgh, UK

19. Paediatric Pathology Department, Royal Infirmary of Edinburgh, Edinburgh, UK

20. Pathology Department, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France

21. Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France

22. Institut National de la Santé et de la Recherche Médicale UMR 1163, Laboratory of Immunogenetics of Paediatric Autoimmunity, Imagine Institute, Paris, France

23. Pediatric Pneumology Department, Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire Lille, Lille, France

24. Cordeliers Research Center, Université Paris Descartes, Université de Paris, UMRS1138 Inflammation, Complement and Cancer Team, Paris, France

25. Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Trousseau University Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France

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.

Funder

Institut National de la Santé et de la Recherche Médicale

La Fondation Square

European Research Council

Agence Nationale de la Recherche

Medical Research Council

Lister Institute of Preventive Medicine

LABEX DCBIOL

Fondation BMS

Agence Nationale de Recherches sur le Sida et les Hépatites Virales

Sidaction

Ile-de-France Emergence