COPA silences STING

Abstract

Two studies published in this issue of JEM, by Lepelley et al. (https://doi.org/10.1084/jem.20200600) and Deng et al. (https://doi.org/10.1084/jem.20201045), and two additional manuscripts by Mukai et al. (https://doi.org/10.1101/2020.05.20.107664 Preprint v1) and Steiner et al. (https://doi.org/10.1101/2020.07.09.194399 Preprint v1) demonstrate that COPA syndrome-associated high interferon titers are linked to mutations in COPA preventing STING's retrieval from the Golgi back to the ER and thereby causing chronic immune activation.

Insights from Sophie Rivara and Andrea Ablasser.

The STING cycle. (A) In resting cells, a basal level of cGAMP promotes the COPII (coatomer complex II)-mediated trafficking of STING from the ER to the Golgi, where STING is recognized by COPA via the adaptor SURF4 to be sent back to the ER through the COPI machinery. (B) In patients carrying a pathogenic COPA mutant, the COPA-driven cargo sorting of STING into COPI vesicles is impaired, leading to STING accumulation in the Golgi, increased downstream signaling, and type I IFN production.