Abstract

3C protease (3Cpro), a chymotrypsin-like cysteine protease encoded by the foot-and-mouth disease virus (FMDV), plays an essential role in processing the FMDV P1 polyprotein into individual viral capsid proteins in FMDV replication. Previously, it has been shown that 3Cpro is involved in the blockage of the host type-I interferon (IFN) responses by FMDV. However, the underlying mechanisms are poorly understood. Here, we demonstrated that the protease activity of 3Cpro contributed to the degradation of RIG-I and MDA5, key cytosolic sensors of the type-I IFN signaling cascade in proteasome, lysosome and caspase-independent manner. And also, we examined the degradation ability on RIG-I and MDA5 of wild-type FMDV 3Cpro and FMDV 3Cpro C142T mutant which is known to significantly alter the enzymatic activity of 3Cpro. The results showed that the FMDV 3Cpro C142T mutant dramatically reduce the degradation of RIG-I and MDA5 due to weakened protease activity. Thus, the protease activity of FMDV 3Cpro governs its RIG-I and MDA5 degradation ability and subsequent negative regulation of the type-I IFN signaling. Importantly, FMD viruses harboring 3Cpro C142T mutant showed the moderate attenuation of FMDV in a pig model. In conclusion, our results indicate that a novel mechanism evolved by FMDV 3Cpro to counteract host type-I IFN responses and a rational approach to virus attenuation that could be utilized for future vaccine development.

Highlights

  • Foot-and-mouth disease virus (FMDV) is a single-stranded positive-sense RNA virus (Kuhn and Wimmer, 1987; Palmenberg, 1990) belonging to genus Aphthovirus and family Picornaviridae (Belsham, 1993), and is a well-known animal viral pathogen

  • In the present work we revealed the exact mechanism by which FMDV 3C protease (3Cpro) mediates the degradation of retinoic acidinducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) and demonstrated that, in the context of cellular type-I IFN signaling, the FMDV 3Cpro C142T substitution moderately attenuated FMDV in a pig model

  • These results suggest that FMDV 3Cpro-mediated RIG-I and MDA5 degradation is governed by the protease activity of FMDV 3Cpro

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Summary

Introduction

Foot-and-mouth disease virus (FMDV) is a single-stranded positive-sense RNA virus (Kuhn and Wimmer, 1987; Palmenberg, 1990) belonging to genus Aphthovirus and family Picornaviridae (Belsham, 1993), and is a well-known animal viral pathogen. The β-ribbon spanning amino acid residues 138–150 of FMDV 3Cpro folds over the peptide binding cleft containing the active site of the enzyme It is involved in determining the degree of flexibility of the enzyme, and influences substrate recognition through direct interaction with substrates bound in the peptide binding cleft (Dragovich et al, 1998; Matthews et al, 1999; Curry et al, 2007). This loop functions to position the substrate correctly for proteolysis, and mutation of Cys142 at the apical tip of the β-ribbon has a momentous impact on the catalytic activity of FMDV 3Cpro (Curry et al, 2007; Sweeney et al, 2007)

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