Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced type I interferon transcription by decreasing interferon regulatory factor 3/7 in protein levels

The leader proteinase (Lpro) of foot-and-mouth disease virus (FMDV) has been identified as an interferon-β (IFN-β) antagonist that disrupts the integrity of transcription factor nuclear factor κB (NF-κB). In this study, we showed that the reduction of double stranded RNA (dsRNA)-induced IFN-α1/β expression caused by Lpro was also associated with a decrease of interferon regulatory factor 3/7 (IRF-3/7) in protein levels, two critical transcription factors for activation of IFN-α/β. Furthermore, overexpression of Lpro significantly reduced the transcription of multiple IRF-responsive genes including 2′,5′-OAS, ISG54, IP-10, and RANTES. Screening Lpro mutants indicated that the ability to process eIF-4G of Lpro is not required for suppressing dsRNA-induced activation of the IFN-α1/β promoter and decreasing IRF-3/7 expression. Taken together, our results demonstrate that, in addition to disrupting NF-κB, Lpro also decreases IRF-3/7 expression to suppress dsRNA-induced type I IFN production, suggesting multiple strategies used by FMDV to counteract the immune response to viral infection.

Research highlights
► FMDV Lpro inhibits poly(I:C)-induced IFN-α1/β mRNA expression.
► Lpro inhibits MDA5-mediated activation of the IFN-α1/β promoter.
► Lpro significantly reduced the transcription of multiple IRF-responsive genes.
► Lpro inhibits IFN-α1/β promoter activation by decreasing IRF-3/7 in protein levels.
► The ability to process eIF-4G of Lpro is not necessary to inhibit IFN-α1/β activation.