IRF8 facilitates bovine ephemeral fever virus replication by downregulating IRF9.

Interferon regulatory factor 8 (IRF8), an essential member of the IRFs protein family, serves as a critical transcriptional regulator in cytokine signaling, gene transcription, and the differentiation and proliferation of immune cells. However, its function on the bovine ephemeral fever virus (BEFV) infection has not been described. In this study, we demonstrate that BEFV infection upregulates the expression of IRF8, and IRF8 promotes the replication of BEFV. Subsequent investigations reveal that IRF8 suppresses the type I IFN signaling pathway via the degradation of IRF9 in the context of BEFV infection. Mechanistically, IRF8 up-regulates NEDD4 Like E3 ubiquitin ligase (NEDD4L) expression, thereby promoting the IRF9 degradation through the ubiquitin-proteasome pathway. Notably, the inhibitory effect of IRF8 on the BEFV-mediated type I IFN signaling pathway was markedly reduced, and the promoting effect of IRF8 on BEFV replication was attenuated in NEDD4L-knockdown cells, unveiling a novel mechanism by which IRF8-NEDD4L-IRF9 axis hijacks type I interferon signaling pathway to facilitate BEFV infection. These findings board valuable insights into the function of IRF8, which may serve as a basis for the design of novel antiviral agents.