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 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 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.