LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP

Extracellular 2′3′-cyclic-GMP-AMP (cGAMP) is an immunotransmitter exported by diseased cells and imported into host cells to activate the innate immune STING pathway. We previously identified SLC19A1 as a cGAMP importer, but its use across human cell lines is limited. Here, we identify LRRC8A heteromeric channels, better known as volume-regulated anion channels (VRAC), as widely expressed cGAMP transporters. LRRC8A forms complexes with LRRC8C and/or LRRC8E, depending on their expression levels, to transport cGAMP and other 2′3′-cyclic dinucleotides. In contrast, LRRC8D inhibits cGAMP transport. We demonstrate that cGAMP is effluxed or influxed via LRRC8 channels, as dictated by the cGAMP electrochemical gradient. Activation of LRRC8A channels, which can occur under diverse stresses, strongly potentiates cGAMP transport. We identify activator sphingosine 1-phosphate and inhibitor DCPIB as chemical tools to manipulate channel-mediated cGAMP transport. Finally, LRRC8A channels are key cGAMP transporters in resting primary human vasculature cells and universal human cGAMP transporters when activated. [Display omitted] •A CRISPR screen identifies human LRRC8A heteromeric channels as cGAMP transporters•Expression of LRRC8A and LRRC8C/E promotes cGAMP transport while LRRC8D inhibits it•Activating LRRC8A channels potentiates transport of cGAMP•Resting primary human vasculature cells use LRRC8A channels to import cGAMP 2′3′-cyclic-GMP-AMP (cGAMP) is a paracrine innate immune messenger. It is produced and exported by cells upon detection of cytosolic dsDNA and imported into neighboring cells to locally activate stimulator of interferon genes (STING). Using a CRISPR screen, Lahey et al. identify LRRC8A channels as widely expressed bi-directional transporters of cGAMP.