Foot-and-Mouth Disease Virus 3C^pro Cleaves BP180 to Induce Blister Formation

Foot-and-mouth disease (FMD) is mainly characterized by blister formation (vesicles) in animals infected with foot-and-mouth disease virus (FMDV). However, the molecular basis of the blister formation in FMD is still unknown. BP180 is one of the main anchoring proteins connecting the dermal and epidermal layers of the skin. Previous studies have shown that the cleavage of BP180 by proteases produced by the inflammatory cells and the resulting skin loosening are major causes of the blister formation in bullous pemphigoid (BP) disease. Similar to BP, here we have demonstrated that, among the FMDV-encoded proteases, only FMDV 3C^pro contributes to the cleavage of BP180 at multiple sites, consequently inducing the degradation of BP180, leading to skin loosening. Additionally, we confirmed that FMDV 3C^pro interacts directly with BP180 and the FMDV 3C^pro C142T mutant, known to have reduced protease activity, is less effective for BP180 degradation than wild-type FMDV 3C^pro. In conclusion, for the first time, our results demonstrate the function of FMDV 3C^pro on the connective-tissue protein BP180 associated with blister formation.