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

Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi to the ER. Mutation of the gene, encoding one of the COP-I subunits (α-COP), causes an immune dysregulatory disease (COPA syndrome). The molecular mechanism by which the impaired retrograde transport results in autoinflammation is not understood. Here we report that STING, an innate immunity protein, is a cargo of the Golgi-to-ER membrane transport. In the presence of the disease-causative 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, 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.