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 Aphthovirus in the family Picornaviridae. FMDV's 3C protein is a nonstructural protein and, moreover, is a protease (3Cpro) that adopts a chymotrypsin-like fold and harbors a Cys-His-Asp catalytic triad. The 3Cpro 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 3Cpro concerning its multiple characteristics, including nucleotide and protein sequences, crystal structures, enzymatic activities, anti-3Cpro inhibitors, and more importantly, its functions in cleaving the viral polyprotein and host proteins. This review aims to provide a comprehensive insight into FMDV 3Cpro as a protease functioning in the course of viral propagation.