LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP
LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP
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LRRC8A：C/E异构体通道是cGAMP普遍存在的转运体
DOI：
10.1016/j.molcel.2020.10.021
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发表时间：
2020-11-19
期刊：
影响因子：
16
通讯作者：
Li, Lingyin
中科院分区：
文献类型：
--
作者：
Lahey, Lauren J.;Mardjuki, Rachel E.;Li, Lingyin
细胞外2 '3'-环-GMP-AMP（cGAMP）是由患病细胞输出并输入宿主细胞以激活先天免疫STING途径的免疫递质。我们先前将SLC 19 A1鉴定为cGAMP输入者，但其在人类细胞系中的使用有限。在这里，我们确定LRRC 8A异聚体通道，更好地称为体积调节阴离子通道（VRAC），作为广泛表达的cGAMP转运蛋白。LRRC 8A与LRRC 8 C和/或LRRC 8 E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'-环二核苷酸。相反，LRRC 8D抑制cGAMP转运。我们证明，cGAMP流出或流入通过LRRC 8通道，由cGAMP电化学梯度。LRRC 8A通道的激活，这可能发生在不同的压力下，强烈增强cGAMP运输。我们确定激活剂鞘氨醇1-磷酸和抑制剂DCPIB作为化学工具来操纵通道介导的cGAMP转运。最后，LRRC 8A通道是静息原代人血管细胞中的关键cGAMP转运蛋白，并且在激活时是通用人cGAMP转运蛋白。
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.