ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP

The DNA sensor cyclic GMP-AMP synthase (cGAS) is important for antiviral and anti-tumor immunity. cGAS generates cyclic GMP-AMP (cGAMP), a diffusible cyclic dinucleotide that activates the antiviral response through the adaptor protein stimulator of interferon genes (STING). cGAMP cannot passively cross cell mem-branes, but recent advances have established a role for extracellular cGAMP as an immunotransmitterthat can be imported into cells. However, the mechanism by which cGAMP exits cells remains unknown. Here, we identifed ABCC1 as a direct, ATP-dependent cGAMP exporter in mouse and human cells. We show that ABCC1 overexpression enhanced cGAMP export and limited STING signaling and that loss of ABCC1 reduced cGAMP export and potentiated STING signaling. We demonstrate that ABCC1 deficiency exacer-bated cGAS-dependent autoimmunity in the Trex1-/- mouse model of Aicardi-Goutieres syndrome. Thus, ABCC1-mediated cGAMP export is a key regulatory mechanism that limits cell-intrinsic activation of STING and ameliorates STING-dependent autoimmune disease.

Automated summary

The DNA sensor cGAS and its product cGAMP play important roles in antiviral and anti-tumor immunity. This study identifies ABCC1 as a direct, ATP-dependent cGAMP exporter and demonstrates that its deficiency exacerbates autoimmune diseases.