Homeostatic regulation of STING by Golgi-to-ER membrane traffic

Abstract

Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi to the ER 1,2 . Mutation of the COPA gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease (COPA syndrome) 3 . The molecular mechanism by which the impaired retrograde transport results in autoinflammation is not understood. Here we report that STING 4 , an innate immunity protein, is a cargo of the Golgi-to-ER membrane transport. In the presence of the diseasecausative α-COP variants, STING cannot be retrieved back to the ER from the Golgi. The forced Golgi residency of STING results in the cGAS-independent and palmitoylation-dependent activation of the STING downstream signalling pathway. Surf4 5 , a protein that circulates between the ER and the Golgi, binds STING and α-COP, and mediates retrograde transport of STING to the ER. STING/Surf4/α-COP complex is disrupted in the presence of the disease-causative α-COP variant. Intriguingly, the STING ligand cGAMP also impairs the formation of STING/Surf4/α-COP complex. Our results suggest a homeostatic regulation of STING at the resting state by the Golgi-to-ER membrane traffic and provide insights into the pathogenesis of COPA syndrome.

Activation of STING due to COPI-deficiency

“…Therefore, retrograde transport of STING would require an adaptor protein. This hypothesis is supported by prepublication data from two laboratories, demonstrating that COPA binding to STING is dependent on Surfeit protein 4 (SURF4) (47,48). This also agrees with our proteomic analysis, where SURF4 and COPA were immunoprecipitated with STING after overexpression in HEK293T cells (Figure 2A).…”

The cGAS–STING pathway as a therapeutic target in inflammatory diseases

“…Meanwhile, recent insights from human genetic studies (see below) have unfolded a mechanism that operates at steady state and actively retrieves STING from the Golgi back to the ER to suppress cellular activation. Specifically, the adaptor protein SURF4 interacts with STING at the Golgi to facilitate STING’s encapsulation into COPI vesicles for retrograde transport 37 , 38 . Although future work needs to refine the molecular coordination of the intracellular destinations of STING, they appear to ultimately converge with STING’s degradation in lysosomes 39 .…”

“…Clinically, patients typically present with inflammatory arthritis, interstitial lung disease and kidney disease and exhibit a type I interferon signature in blood — features that are to some degree reminiscent of SAVI 132 . Recently, four independent studies have shown that defects caused by COPA mutations promote ligand-independent activation of STING-mediated signalling and that the elevated type I interferon signature associated with COPA dysfunction can be reduced by genetic or pharmacological interference with STING 37 , 38 , 133 , 134 . In a mouse model of COPA syndrome ( Copa E241K/+ ), type I interferon-driven inflammation was rescued by crossing these mice with STING-deficient ( STING gt/gt ) animals and, moreover, the embryonic lethality of homozygous Copa E241K/E241K mice was rescued by co-deletion of STING 37 .…”

COPA silences STING

“…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.…”