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

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.

COPA silences STING

“…In their complementary work, the group of Anthony K. Shum and colleagues (Deng et al, 2020) highlight additional insights into the mechanism underlying STING's involvement in the disease and, in addition, provide in vivo proof-of-concept studies on potential pharmacological treatment options. After confirming STING's activation (phosphorylation and localization to the Golgi) in lung fibroblasts from a COPA patient, they show, similar to the results of Lepelley et al (2020), that STING associates with COPA, which is reduced when tested with mutant COPA. Given that STING lacks the COPA-recognized dilysine motif, their results pointed toward another (transmembrane) protein acting as an adaptor to mediate the STING-COPA interaction.…”

“…Recent advances in the understanding of STING trafficking regulation included the identification of several STING interactors, notably STIM1, involved in its retention in the ER (Srikanth et al, 2019), and STEEP (STING ER exit protein), reportedly essential to load STING into CO-PII vesicles (Zhang et al, 2020). However, whereas these and other previous publications center around the ER enrichment and the anterograde ER-to-Golgi trafficking of STING, the work published in Lepelley et al, 2020 andDeng et al, 2020 in this issue of JEM as well as the work in Mukai et al, 2020 (Preprint) and Steiner et al, 2020 (Preprint) highlight that the regulation of STING "going back"overlooked so far-is as important as the one set in place of "going forward." For future work, it would be interesting to investigate whether a similar adaptor-effector tandem (SURF-COPA equivalent) exists for COPII and anterograde trafficking.…”

“…Given the similarities in the clinical presentations of SAVI and COPA syndrome on the one hand and the overlapping aspect of ER-Golgi/Golgi-ER trafficking on the other hand, the four groups (Deng et al, 2020;Lepelley et al, 2020;Mukai et al, 2020 Preprint;Steiner et al, 2020 Preprint) investigated whether the missing link between COPA mutations and high type I IFN titers might be STING.…”

“…The group of Yanick J. Crow and colleagues (Lepelley et al, 2020) extensively characterized nine carriers of pathogenic COPA variants. In doing so, they confirmed the similarities between COPA syndrome and SAVI: interstitial lung disease and chronic up-regulation of type I IFN, as evidenced by activated STAT1 signaling as well as high expression levels of several IFNinduced genes (ISGs).…”

“…It hence has to associate with proteins it sends back toward the ER. To test for a potential interaction with STING, Lepelley et al (2020) performed immunoprecipitation experiments and confirmed an interaction between STING and COPA, which was reduced when COPA mutants were used. The authors mapped the transmembrane region of STING as critical for this interaction and, furthermore, demonstrated by confocal fluorescence microscopy that expression of COPA mutants caused STING to accumulate in the Golgi, whereas COPA overexpression did not affect the localization of STING in the ER.…”