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

Heterozygous missense mutations in coatomer protein subunit ?, 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-? 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.
Mesh Terms:
Adolescent, Adult, Child, Coatomer Protein, Endoplasmic Reticulum, Female, Gene Knockout Techniques, Golgi Apparatus, HEK293 Cells, Humans, Interferon Type I, Male, Membrane Proteins, Middle Aged, Mutation, Missense, Protein Transport, Signal Transduction, THP-1 Cells, Transfection, Young Adult
J Exp Med
Date: Dec. 02, 2019
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