The Foot-and-Mouth Disease Virus Lb Protease Cleaves Intracellular Transcription Factors STAT1 and STAT2 to Antagonize IFN-β–Induced Signaling

Abstract

Foot-and-mouth disease virus (FMDV) is the causative agent of foot-and-mouth disease, one of the most highly infectious animal viruses throughout the world. The JAK-STAT signaling pathway is a highly conserved pathway for IFN-β–induced antiviral gene expression. Previous studies have shown that FMDV can strongly suppress the innate immune response. Moreover, although STAT1 and STAT2 (STAT1/2) have been well established in JAK-STAT signaling–induced antiviral gene expression, whether FMDV proteins inhibit IFN-β–induced JAK-STAT signaling remains poorly understood. In this study, we described the Lb leader protease (Lbpro) of FMDV as a candidate for inhibiting IFN-β–induced signaling transduction via directly interacting with STAT1/2. We further showed that Lbpro colocalized with STAT1/2 to inhibit their nuclear translocation. Importantly, Lbpro cleaved STAT1/2 to inhibit IFN-β–induced signal transduction, whereas the catalytically inactive mutant of LC51A (Lbpro with cysteine substituted with alanine at amino acid residue 51) had no effect on the stability of STAT1/2 proteins. The cleavage of the STAT1/2 proteins was also determined during FMDV infection in vitro. Lbpro could cleave the residues between 252 and 502 aa for STAT1 and the site spanning residues 140 − 150 aa (QQHEIESRIL) for STAT2. The in vivo results showed that Lbpro can cleave STAT1/2 in pigs. Overall, our findings suggest that FMDV Lbpro–mediated targeting of STAT1/2 may reveal a novel mechanism for viral immune evasion.

Host-Specific Interplay between Foot-and-Mouth Disease Virus 3D Polymerase and the Type-I Interferon Pathway

“…Indeed, the interactions between Lb pro and TRAF3 and MDA5, and between 3A and MAVS, MDA5 and RIG-I, already shown in a human model, were confirmed from their bovine versions for the first ones, and from bovine and porcine versions for the three others [ 44 , 45 , 46 , 47 ]. The same is true for the 3C–MDA5, 3C–NEMO, Lb pro –STAT1/2 and Lab pro –IRF7 interactions, which were already demonstrated using porcine proteins and which were found in both the screenings carried out within this study using the porcine and bovine libraries [ 48 , 49 , 50 , 51 ]. While the interaction described between Lab pro and swine IRF3 was not found using its bovine version, bovine IRF3 was identified as interacting with the alternative leader protein form Lb pro [ 50 ].…”

Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine of IFNα and is enhanced by CD47 blockade

“…Although IFNAR1 has relatively weak ligand binding a nity, it initiates intracellular signal cascades and provides docking sites for signal transducers and transcriptional activators. Upon stimulation by IFNα, heterodimers of STAT1 and STAT2 migrate to the nucleus, where they induce the expression of ISGs [45][46][47]. Blocking IFNAR or using IFNAR-/-mice abolishes the antitumor effect of F1/F3 (Fig.…”