STAT6 promotes innate immunity against BEFV and VSV by inhibiting STUB1 and NIX-mediated MAVS degradation

Signal transducers and activators of transcription 6 (STAT6), an essential member of the STAT protein family, plays vital roles in innate immunity, however, its function in regulating innate immunity through the degradation of MAVS has not been described. In this study, we found that STAT6 suppresses the replication of both bovine ephemeral fever virus (BEFV) and vesicular stomatitis virus (VSV). Further investigations revealed that STAT6 promotes the type I IFN (IFN-I) signaling pathway in the context of BEFV and VSV infection. Moreover, the knockout of STAT6 leads to the degradation of MAVS through both the ubiquitin-proteasome and autophagolysosomal pathways. Mechanistically, STAT6 results in the downregulation of E3 ubiquitin ligase STIP1 homology and Ubox-containing protein 1 (STUB1), inhibits the interaction between STUB1 and MAVS, and reduces STUB1- mediated K48-linked MAVS ubiquitination, thereby inhibiting the MAVS degradation through the ubiquitin-proteasome pathway. Furthermore, STAT6 also suppresses MAVS degradation through the autophagy receptor Bcl2 interacting protein 3 like (NIX)-mediated autophagy pathway. Taken together, our study unveils a novel mechanism by which STAT6 acts as a positive regulator of the type I IFN signaling pathway during BEFV and VSV infection, predominantly by inhibiting MAVS degradation and ultimately suppressing BEFV and VSV infection. These findings provide valuable insights into the regulation of MAVS degradation by STAT6, which may serve as a basis for the design of novel antiviral agents.