Abstract：
DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2\'3\'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces innate immunity. cGAMP not only activates STING in the cell where it is produced but cGAMP also transfers to other cells. Transporters, channels, and pores (including SLC19A1, SLC46A2, P2X7, ABCC1, and volume-regulated anion channels (VRACs)) release cGAMP into the extracellular space and/or import cGAMP. We report that infection with multiple human viruses depletes some of these cGAMP conduits. This includes herpes simplex virus 1 (HSV-1) that targets SLC46A2, P2X7, and the VRAC subunits LRRC8A and LRRC8C for degradation. The HSV-1 protein UL56 is necessary and sufficient for these effects that are mediated at least partially by proteasomal turnover. UL56 thereby inhibits cGAMP uptake via VRAC, SLC46A2, and P2X7. Taken together, HSV-1 antagonizes intercellular cGAMP transfer. We propose that this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.
摘要：
DNA传感对于抗病毒免疫是重要的。DNA传感器cGAS合成2'3'-环GMP-AMP（cGAMP），激活STING的第二个信使，诱导先天免疫。cGAMP不仅在产生它的细胞中激活STING,而且cGAMP还转移到其他细胞。运输商,频道,孔（包括SLC19A1，SLC46A2，P2X7，ABCC1和体积调节阴离子通道（VRAC））将cGAMP释放到细胞外空间和/或输入cGAMP。我们报告说，多种人类病毒感染会耗尽其中一些cGAMP导管。这包括靶向SLC46A2、P2X7和用于降解的VRAC亚基LRRC8A和LRRC8C的单纯疱疹病毒1(HSV-1)。HSV-1蛋白UL56对于这些至少部分由蛋白酶体更新介导的作用是必要和足够的。UL56通过VRAC抑制cGAMP摄取，SLC46A2和P2X7。一起来看,HSV-1拮抗细胞间cGAMP转移。我们认为，这通过减少经由免疫转导cGAMP的细胞间通讯来限制先天免疫。
