SNX8 interacts with THOC7 to negatively regulate IFN 1 response via the TBK1-IRF3 signaling axis in teleost fish

Teleost sorting nexin 8 (SNX8) negatively regulates antiviral innate immunity, but its precise mechanism remains unclear. Here, using IP and LC-MS/MS analyses, we identified grass carp THOC7 (CiTHOC7) as a candidate protein that interacts with SNX8. THOC7 was significantly up-regulated in all tested tissues following GCRV infection. Moreover, THOC7 suppressed virus-induced IFN 1 signaling, aggravated GCRV-induced developmental abnormalities of zebrafish embryos, and reduced their survival rates. Further investigations demonstrated that SNX8 interacted with THOC7, facilitated its phosphorylation, and promoted the association between THOC7 and TBK1, thereby suppressing TBK1 phosphorylation. Either THOC7 alone or SNX8 collaborated with THOC7 significantly suppressed GCRV-induced irf3, irf7, and ifn 1 gene transcription, IFN 1 promoter and ISRE activation, as well as IRF7 expression and IFN 1 production. Additionally, they attenuated phosphorylation of TBK1 and IRF3, while affecting IRF7 expression but not its phosphorylation. Collectively, these findings indicated that SNX8 cooperates with THOC7 to negatively regulate the IFN 1 response through the TBK1-IRF3 signaling axis, providing novel insights into the regulatory mechanism of antiviral innate immunity in grass carp.