The intracellular membrane-tethered protein STING couples sensors of the innate immune system to the production of type I interferon by facilitating activation of the transcription factor IRF3 by the kinase TBK1. In Cell, Konno et al. identify a feedback regulatory mechanism that prevents sustained activation of STING and inflammatory disease. STING is activated by cyclic guanosine or adenosine dinucleotides (cGAMP) that are generated by cGAMP synthase (cGAS) after aberrant nucleic acids are detected. Cyclic dinucleotides likewise bind to the kinase AMPK, which acts as a suppressor of the autophagy protein ULK1 (ATG1). cGAMP causes AMPK to release tethered ULK1 that then phosphorylates STING, specifically on Ser366, and induces its degradation in lysosomes. ULK1-mediated targeting of STING thus prevents further activation of IRF3 and terminates the expression of type I interferon.

Cell 155, 688–698 (2013)