RT Journal Article
SR Electronic
T1 ABCC1/MRP1 exports cGAMP and modulates cGAS-dependent immunity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.03.470980
DO 10.1101/2021.12.03.470980
A1 Joanna H. Maltbaek
A1 Jessica M. Snyder
A1 Daniel B. Stetson
YR 2021
UL http://biorxiv.org/content/early/2021/12/03/2021.12.03.470980.abstract
AB 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 adapter protein Stimulator of Interferon Genes (STING). cGAMP is negatively charged and cannot passively cross cell membranes, but recent advances have established a role for extracellular cGAMP as an “immunotransmitter” that can be imported into cells. However, the mechanism by which cGAMP exits cells remains unknown. Here, we identify ABCC1/MRP1 as an ATP-dependent cGAMP exporter that influences STING signaling and type I interferon production. We demonstrate that ABCC1 deficiency exacerbates cGAS-dependent autoimmunity in the Trex1-/- mouse model of Aicardi-Goutières syndrome. These studies identify ABCC1-mediated cGAMP export as a key regulatory mechanism of the cGAS-STING pathway.Competing Interest StatementD.B.S. is a co-founder and shareholder of Danger Bio, LLC, and a scientific advisor for Related Sciences, LLC.