Xu Xiaowen, Li Meifeng, Deng Zeyuan, Jiang Zeyin, Li Dongming, Wang Shanghong, Hu Chengyu
College of Life Science, Nanchang University; Nanchang, 330031, Jiangxi, China.
College of Life Science, Nanchang University; Nanchang, 330031, Jiangxi, China.
Dev Comp Immunol. 2021 Dec;125:104233. doi: 10.1016/j.dci.2021.104233. Epub 2021 Aug 14.
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.
环鸟苷酸-腺苷酸合成酶（cGAS）是一种已知的DNA传感器，可引发人类和其他哺乳动物的先天性免疫反应。然而，关于鱼类cGAS的知识有限。在本研究中，我们从草鱼（Ctenopharyngodon idellus）中鉴定出cGAS基因的两个旁系同源基因，即CicGASa和CicGASb。草鱼cGASa和cGASb与哺乳动物cGAS具有一些保守结构域；然而，cGASb含有一个独特的跨膜结构域。草鱼cGASa和cGASb对草鱼呼肠孤病毒（GCRV）和聚（dA:dT）感染有反应，但它们在I型干扰素反应的调节中发挥相反作用，即cGASa以剂量依赖方式作为干扰素刺激基因（ISGs）和核因子κB（NF-κB）的激活剂，而cGASb则作为抑制剂。我们发现cGASa和cGASb与干扰素基因刺激蛋白（STING）相互作用。同样，cGASa是干扰素调节因子7（IRF7）的激活剂，但cGASb抑制IRF7表达。cGASa和STING都可以保护细胞免受GCRV感染。草鱼cGASb通过与STING的竞争性相互作用抑制cGASa诱导的I型干扰素反应，这表明cGASb可能是cGASa-STING-IRF7轴的负调节因子。
