Singapore grouper iridovirus VP018 exploits FTR86 to promote viral replication through Tollip-mediated degradation of the STING-TBK1 axis

Members of the tripartite motif (TRIM) family have been demonstrated to exert crucial roles in immune defense against pathogens. However, functions of the fish-specific TRIM subfamily (FTR), which lacks mammalian orthologues, remains poorly understood. In the current study, we investigated the potential roles of grouper FTR86 (EcFTR86) on innate immune response and its actions during fish virus infection. EcFTR86 was found to localize to lysosomes, and its transcription was significantly up-regulated in grouper spleen cells upon Singapore grouper iridovirus (SGIV) infection. Notably, the exogenous expression of EcFTR86 markedly enhanced SGIV replication, whereas knockdown of endogenous EcFTR86 significantly attenuated viral infection, demonstrating that EcFTR86 functions as a pro-viral factor against virus infection. EcFTR86 negatively regulated type I interferon signaling triggered by STING-TBK1 and interacted with the key molecules of STING-TBKl axis. Mechanistically, EcFTR86 degraded STING or TBK1 via an autophagy-lysosome-dependent pathway. Moreover, autophagic cargo receptor Tollip was identified to interact with EcFTR86, and was involved in EcFTR86-mediated degradation of STING or TBK1. In addition, EcFTR86 was verified to interact with SGIV viral proteins, including VP018 and VP075, whereas only VP018 exploited EcFTR86 to accelerate the degradation effects on STING and TBK1, thereby abrogating the interferon response. Collectively, our findings firstly showed that FTR86 functioned as a negative regulator of interferon response, and was exploited by fish iridoviral proteins to promote viral replication via Tollip-mediated autophagic degradation of the STING-TBK1 axis.