A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome

Abstract

Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi–ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon–driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.

COPA silences STING

“…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.…”

“…All in all, the insight provided in Deng et al, 2020, Lepelley et al, 2020, Mukai et al, 2020, and Steiner et al, 2020 (Preprint) not only opens the door to novel treatment approaches for COPA syndrome, but it also advances understanding on the intricate mechanisms regulating STING activation and 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.…”

“…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.…”

“…Of note, the embryonic lethality of homozygous Copa E241K/E241K mice could be rescued by a deletion of STING (Copa E241K/+ ×Sting gt/gt parents). Based on these findings, Deng et al (2020) reasoned that STING inhibition could have therapeutic benefits. Treating splenocytes from Copa E241K/+ mice and peripheral blood mononuclear cells from a COPA syndrome patient with small molecular inhibitors of STING (Haag et al, 2018) or with a JAK-STAT inhibitor (targeting a signaling step downstream of type I IFN production) indeed decreased ISG levels, but only the STING inhibitors reduced type I IFN expression.…”