Grass carp reovirus VP6 inhibits IFN production by degrading TBK1 through the autophagy pathway.

The interferon (IFN) response serves as a powerful defense mechanism against viral infections in fish. However, grass carp reovirus (GCRV) is capable of evading the IFN system, although the specific mechanisms remain unclear. In this study, we report that GCRV VP6 employs an immune evasion strategy by degrading TANK-binding kinase 1 (TBK1) through the autophagy pathway, thereby inhibiting IFN activation. Firstly, overexpression of VP6 facilitated the replication of GCRV, while, it impeded the activation of the IFN promoter induced by polyinosinic-polycytidylic acid (poly I:C) and GCRV. In addition, VP6 was found to interact with TBK1 and suppress its expression. Treatment with autophagy pathway inhibitors was able to restore TBK1 degradation, indicating that VP6 degrades TBK1 through the autophagy pathway. Furthermore, VP6 significantly attenuated the cellular antiviral response mediated by TBK1, thereby suppressing IFN production. These results demonstrate how GCRV evades the host immune response by exploiting the host autophagy system and provide insight into the underlying molecular mechanisms involved.