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.

细胞外 2'3'-环 GMP-AMP (cGAMP) 是一种免疫递质，由患病细胞输出并输入宿主细胞以激活先天免疫 STING 通路。我们之前将 SLC19A1 确定为 cGAMP 进口商，但它在人类细胞系中的使用是有限的。在这里，我们确定 LRRC8A 异聚通道，更广为人知的是体积调节阴离子通道 (VRAC)，作为广泛表达的 cGAMP 转运蛋白。LRRC8A 与 LRRC8C 和/或 LRRC8E 形成复合物，这取决于它们的表达水平，以转运 cGAMP 和其他 2'3'-环状二核苷酸。相反，LRRC8D 抑制 cGAMP 转运。我们证明 cGAMP 通过 LRRC8 通道流出或流入，如 cGAMP 电化学梯度所指示。LRRC8A 通道的激活（可在不同压力下发生）强烈增强 cGAMP 转运。我们将激活剂 1-磷酸鞘氨醇和抑制剂 DCPIB 确定为操纵通道介导的 cGAMP 转运的化学工具。最后，LRRC8A 通道是静息原代人类血管系统细胞和通用人类 cGAMP 转运蛋白激活时的关键 cGAMP 转运蛋白。