最近发现，细胞外 2'-3'cGAMP 可以通过叶酸转运蛋白 SLC19A1 跨细胞膜转运，以不依赖于 cGAS 的方式激活 STING 通路，SLC19A1 是癌细胞中第一个发现的这种关键信号分子的细胞外反向转运蛋白。我们假设 STING 通路的这种非典型激活将起到建立类似于干扰素旁分泌抗病毒活性的抗病毒状态的作用。在此，我们报告用外源 2'-3'cGAMP 处理单核细胞系、THP-1 细胞和 SH-SY5Y 神经元细胞系可诱导干扰素产生并建立限制单纯疱疹病毒 1 (HSV-1) 的抗病毒状态。 ），一种在人群中具有高血清阳性率的普遍存在的病毒。使用药物抑制或基因敲除 SLC19A1 可阻断 2'-3'cGAMP 诱导的病毒复制抑制。我们的数据表明 SLC19A1 作为新鉴定的细胞外 2'-3'cGAMP 抗病毒介质发挥作用。这项工作提出了关于抗病毒机制的新颖而重要的发现，这些信息可以帮助未来开发更好的抗病毒药物。版权所有 © 2024。由 Elsevier B.V. 出版。

Recently it was discovered that extracellular 2'-3'cGAMP can activate the STING pathway in a cGAS-independent fashion by being transported across the cell membrane via the folate transporter, SLC19A1, the first identified extracellular antiporter of this critical signaling molecule in cancer cells. We hypothesized that this non-canonical activation of STING pathway would function to establish an antiviral state similar to that seen with the paracrine antiviral activities of interferon. Herein, we report that treatment of the monocytic cell line, THP-1 cells and SH-SY5Y neuronal cell line with exogenous 2'-3'cGAMP induces interferon production and establishes an antiviral state that limits herpes simplex virus-1 (HSV-1), a ubiquitous virus with high seropositivity in the human population. Using either pharmaceutical inhibition or genetic knockout of SLC19A1 blocks the 2'-3'cGAMP-induced inhibition of viral replication. Our data indicate SLC19A1 functions as a newly identified antiviral mediator for extracellular 2'-3'cGAMP. This work presents novel and important findings about an antiviral mechanism which information could aid in the development of better antiviral drugs in the future.Copyright © 2024. Published by Elsevier B.V.