Peptidyl-prolyl isomerase B suppresses BEFV- and VSV-induced type I interferon responses via degradation of PBLD.

Peptidyl-prolyl isomerase B (PPIB), a member of the peptidyl-prolyl cis-trans isomerase family, is well-documented to facilitate viral propagation by interactions with viral proteins. However, its regulatory roles in the replication of bovine ephemeral fever virus (BEFV) or vesicular stomatitis virus (VSV), as well as in host innate immune responses remain unexplored. In this study, we demonstrate that PPIB enhances the replication of BEFV and VSV and suppresses the host type I interferon (IFN-I) response. Mechanistically, PPIB interacts with phenazine biosynthesis-like domain-containing protein (PBLD), a positive regulator of innate immunity, and triggers its degradation via the ubiquitin-proteasome pathway. Further analyses showed that PPIB enhances the interaction between the E3 ubiquitin ligase March2 and PBLD, thereby facilitating PBLD ubiquitination and subsequent degradation. This PPIB-mediated, March2-dependent degradation of PBLD inhibits IFN-I production, ultimately enhancing viral replication. Collectively, our findings unveil an unrecognized role of PPIB in regulating IFN-I responses and viral replication through the PPIB-March2-PBLD signaling axis, providing novel insights for the development of broad-spectrum antiviral therapeutics.