Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.
Lepelley A,Martin-Niclós M,Le Bihan M,Marsh J,Uggenti C,Rice G,Bondet V,Duffy D,Hertzog J,Rehwinkel J,Amselem S,Boulisfane-El Khalifi S,Brennan M,Carter E,Chatenoud L,Chhun S,Coulomb l'Hermine A,Depp M,Legendre M,Mackenzie K,Marey J,McDougall C,McKenzie K,Molina T,Neven B,Seabra L,Thumerelle C,Wislez M,Nathan N,Manel N,Crow Y,Frémond M
Source :
The journal of experimental medicine 2020
2020 Jul 30
Pmid / DOI:
32725128
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.© 2020 Lepelley et al.