Cyclic GMP-AMP synthase (cGAS) is known as a DNA sensor for the initiation of innate immune responses in human and other mammals. However, the knowledge about fish cGAS is limited. In this study, we identified two paralogs of cGAS genes from grass carp (Ctenopharyngodon idellus), namely, CicGASa and CicGASb. Grass carp cGASa and cGASb share some conservative domains with mammalian cGASs; however, cGASb contains a unique transmembrane domain. Grass carp cGASa and cGASb responded to GCRV and poly (dA:dT) infection, but they played opposite roles in the regulation of type I IFN response, i.e. cGASa served as an activator for ISGs and NF-κB in a dose-dependent manner, while cGASb acted as an inhibitor. We found that cGASa and cGASb interacted with STING. Similarly, cGASa is an activator for IRF7, but cGASb inhibited IRF7 expression. Both cGASa and STING can protect cells from GCRV infection. Grass carp cGASb inhibited cGASa-induced type I IFN response by the competitive interaction with STING, suggesting that cGASb may be a negative regulator of cGASa-STING-IRF7 axis.

环状 GMP-AMP 合酶 (cGAS) 被称为 DNA 传感器，用于启动人类和其他哺乳动物的先天免疫反应。然而，关于鱼类 cGAS 的知识是有限的。在本研究中，我们从草鱼 ( Ctenopharyngodon idellus ) 中鉴定了两个 cGAS 基因旁系同源物，即CicGASa和CicGASb. 草鱼 cGASa 和 cGASb 与哺乳动物 cGAS 共享一些保守结构域；然而，cGASb 包含一个独特的跨膜结构域。草鱼 cGASa 和 cGASb 对 GCRV 和 poly (dA:dT) 感染有反应，但它们在 I 型 IFN 反应的调节中起相反的作用，即 cGASa 以剂量依赖性方式作为 ISGs 和 NF-κB 的激活剂，而 cGASb 起抑制剂的作用。我们发现 cGASa 和 cGASb 与 STING 相互作用。类似地，cGASa 是 IRF7 的激活剂，但 cGASb 抑制 IRF7 的表达。cGASa 和 STING 都可以保护细胞免受 GCRV 感染。草鱼cGASb通过与STING竞争性相互作用抑制cGASa诱导的I型IFN反应，提示cGASb可能是cGASa-STING-IRF7轴的负调节因子。