BmCPV replication is suppressed by the activation of the NF-κB/autophagy pathway through the interaction of vsp21 translated by vcircRNA_000048 with ubiquitin carboxyl-terminal hydrolase.

Bombyx mori cypovirus (BmCPV), a typical double-stranded RNA virus, was demonstrated to generate a viral circRNA, vcircRNA_000048, which encodes a vsp21 with 21 amino acid residues to suppress viral replication. However, the regulatory mechanism of vsp21 on virus infection remained unclear. This study discovered that vsp21 induces reactive oxygen species (ROS) generation, activates autophagy, and attenuates virus replication by inducing autophagy. Then we confirmed that the effect of vsp21-induced autophagy on viral replication was attributed to the activation of the NF-κB signaling pathway. Furthermore, we clarified that vsp21 interacted with ubiquitin carboxyl-terminal hydrolase (UCH) and that ubiquitination and degradation of phospho-IκB-α were enhanced by vsp21 via competitive binding to UCH. Finally, we validated that vsp21 activates the NF-κB/autophagy pathway to suppress viral replication by interacting with UCH. These findings provided new insights into regulating viral multiplication and reovirus-host interaction.