Varicellovirus bovinealpha 1 UL42 targets host IRF3 to inhibit type I interferon β production

Varicellovirus bovinealpha 1 (formerly bovine alphaherpesvirus type 1, BoAHV-1), a significant pathogen in cattle with substantial economic impacts, establishes lifelong latency and employs multiple immune evasion strategies. In this study, we identified the BoAHV-1 nonstructural protein UL42 as a modulator of the cGAS-STING pathway that suppresses type I interferon β (IFN-β) production. Besides, we find that bovine IRF3 only contains four conserved serine/threonine residues at the C-terminus and its mutant named as IRF3-4D resembles IRF3-5D of other species to retain nuclear localization capability and transcriptional activity. Mechanistically, BoAHV-1 UL42 directly interacts with IRF3 and disrupts the binding of IRF3 to IFN-β promoter without affecting IRF3 phosphorylation or nuclear translocation, thereby inhibiting IFN-β transcription and downstream interferon-stimulated gene (ISG) expression. Further analysis revealed that residues Arg282 and Arg283 of UL42 are critical for its immunosuppressive activity. Together, our results identify BoAHV-1 UL42 as a critical protein that specifically disrupts IRF3-mediated IFN-β production signaling to subvert host antiviral responses.