Mechanisms of cGAMP export

Project Summary/Abstract The cGAS-cGAMP-STING DNA sensing pathway has emerged as a key innate immune response that is important for antiviral immunity, contributes to autoimmune diseases, and mediates aspects of antitumor immunity. cGAMP is a cyclic dinucleotide second messenger that cannot enter or exit cells on its own because

of its strong negative charge, leading the vast majority of studies of cGAMP biology to focus solely on intracellular dynamics of cGAMP. However, very recent advances have established that extracellular cGAMP is a potent “immunotransmitter” that can be imported through a number of transmembrane channels to mediate

STING signaling over a distance. A fundamental question is how cGAMP exits cells to become an extracellular immunotransmitter, but the molecular mechanisms of cGAMP export are completely unknown. We have found that cGAMP is actively exported from live cells, independent of cell death. We have identified the ATP-binding cassette (ABC) transporter ABCC1/MRP1 as a channel that mediates active cGAMP

export. Our studies will explore the cell biological and biochemical mechanisms of ABCC1-mediated cGAMP export, and will test the in vivo function of cGAMP export in a mouse model of cGAS-dependent autoimmune disease. By defining a novel mechanism of cGAMP export, our studies will have important implications for

therapeutics that aim to block cGAS responses in autoimmune disease or enhance STING signaling in tumors.