LRRC8A:C/E 异型通道是 cGAMP 的普遍转运体。
LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP.
机构信息
Biophysics Program, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA; Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
出版信息
Mol Cell. 2020 Nov 19;80(4):578-591.e5. doi: 10.1016/j.molcel.2020.10.021. Epub 2020 Nov 9.
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'-环鸟苷酸-腺苷酸（cGAMP）是一种由病变细胞输出并被宿主细胞摄取的免疫递质，可激活先天免疫 STING 途径。我们之前鉴定了 SLC19A1 是 cGAMP 的摄取器，但它在人类细胞系中的应用受到限制。在这里，我们鉴定了 LRRC8A 同型通道，也称为体积调节阴离子通道（VRAC），是广泛表达的 cGAMP 转运蛋白。LRRC8A 与 LRRC8C 和/或 LRRC8E 形成复合物，具体取决于其表达水平，以转运 cGAMP 和其他 2'3'-环二核苷酸。相比之下，LRRC8D 抑制 cGAMP 的转运。我们证明，根据 cGAMP 的电化学梯度，cGAMP 通过 LRRC8 通道被外排或内流。LRRC8A 通道的激活（可能发生在多种应激下）强烈增强了 cGAMP 的转运。我们鉴定出激活剂鞘氨醇 1-磷酸和抑制剂 DCPIB 是用于操纵通道介导的 cGAMP 转运的化学工具。最后，LRRC8A 通道是静息原发性人血管细胞中的关键 cGAMP 转运蛋白，也是激活后的通用人 cGAMP 转运蛋白。
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