Foot-and-mouth disease virus 3C protease as virulence determinant plays multiple roles in cleaving viral polyprotein and host factors

Foot-and-mouth disease virus (FMDV) can cause a severe infectious disease that primarily affects even-toed ungulates. FMDV is classified into the genus of <i>Aphthovirus</i> in the family <i>Picornaviridae</i>. FMDV's 3C protein is a nonstructural protein and, moreover, is a protease (3C^pro) that adopts a chymotrypsin-like fold and harbors a Cys-His-Asp catalytic triad. The 3C^pro plays crucial roles not only in cleaving the FMDV polyprotein but also in degrading various host proteins. Cleavage of the polyprotein contributes to generating different viral polypeptides. Degradation of host proteins possibly affects cellular signaling pathways, making FMDV impair innate immune responses. Here, we systematically reviewed FMDV 3C^pro concerning its multiple characteristics, including nucleotide and protein sequences, crystal structures, enzymatic activities, anti-3C^pro inhibitors, and more importantly, its functions in cleaving the viral polyprotein and host proteins. This review aims to provide a comprehensive insight into FMDV 3C^pro as a protease functioning in the course of viral propagation.