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.