Homeostatic regulation of STING by retrograde membrane traffic to the ER

Coat protein complex I (COP-I) mediates the retrograde transport from the Golgi apparatus to the endoplasmic reticulum (ER). Mutation of the COPA gene, encoding one of the COP-I subunits (alpha -COP), causes an immune dysregulatory disease known as COPA syndrome. The molecular mechanism by which the impaired retrograde transport results in autoinflammation remains poorly understood. Here we report that STING, an innate immunity protein, is a cargo of the retrograde membrane transport. In the presence of the disease-causative alpha -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 signaling pathway. Surf4, a protein that circulates between the ER/ ER-Golgi intermediate compartment/ Golgi, binds STING and alpha -COP, and mediates the retrograde transport of STING to the ER. The STING/Surf4/alpha -COP complex is disrupted in the presence of the disease-causative alpha -COP variant. We also find that the STING ligand cGAMP impairs the formation of the STING/Surf4/alpha -COP complex. Our results suggest a homeostatic regulation of STING at the resting state by retrograde membrane traffic and provide insights into the pathogenesis of COPA syndrome. COPA regulates Golgi to ER transport, and mutations lead to autoinflammation and disease through poorly understood mechanisms. Here, the authors show that disease-causing COPA variants prevent STING transport from the Golgi to the ER, leading to cGAS-independent activation of the STING pathway.

Automated summary

COPA mediates Golgi to ER transport, with mutations causing autoinflammation and disease through unclear mechanisms. Here, authors show that disease-causing COPA variants prevent STING transport from Golgi to ER, resulting in cGAS-independent activation of STING pathway.