cGASa and cGASb from grass carp (Ctenopharyngodon idellus) play opposite roles in mediating type I interferon response.

Abstract 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.