期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 217, 期 11, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20200600
关键词
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资金
- Institut National de la Sante et de la Recherche Medicale [000427993]
- La Fondation Square
- European Research Council [GA309449, 786142-E-T1IFNs]
- Agence Nationale de la Recherche under the Investments for the Future program [ANR10-IAHU-01]
- Agence Nationale de la Recherche [CE17001002]
- Medical Research Council Career Development Award [MR/M02122X/1]
- LABEX DCBIOL [ANR-10-IDEX-0001-02 PSL*, ANR-11-LABX0043, ANR-17-CE15-0025-01, ANR-18-CE92-0022-01]
- Fondation BMS
- Agence Nationale de Recherches sur le Sida et les Hepatites Virales [ECTZ71745]
- Sidaction [VIH2016126002]
- Ile-de-France Emergence
- Ile-de-France ARDoc
- Lister Institute of Preventive Medicine
- MSDAVENIR (Devo-Decode Project)
- MRC [MR/M02122X/1, MC_UU_00008/8] Funding Source: UKRI
- Agence Nationale de la Recherche (ANR) [ANR-18-CE92-0022, ANR-17-CE15-0025] Funding Source: Agence Nationale de la Recherche (ANR)
Heterozygous missense mutations in coatomer protein subunit a, 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-a 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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