Abstract
Foot-and-mouth disease (FMD), induced by the foot-and-mouth disease virus (FMDV), is a highly contagious disease of cloven-hoofed animals. Previous studies have reported that FMDV 3C protease could degrade multiple host proteins; however, the degradation mechanism mediated by FMDV 3C is still unclear. Here, we found that transient expression of FMDV 3C degraded various molecules in NF-κB signaling in a dose-dependent manner, and the proteolytic activity of FMDV 3C is important for inducing degradation. Additionally, 3C-overexpression was associated with the induction of apoptosis. In this study, we showed that an apoptosis inhibitor CrmA abolished the ability of 3C to degrade molecules in NF-κB signaling. Further experiments using specific caspase inhibitors confirmed the irrelevance of caspase3, caspase8, and caspase9 activity for degradation induced by 3C. Altogether, these results suggest that FMDV 3C induces the widespread degradation of host proteins through its proteolytic activity and that the apoptosis pathway might be an important strategy to mediate this process. Further exploration of the relationship between apoptosis and degradation induced by 3C could provide novel insights into the pathogenic mechanisms of FMDV.
Highlights
Eschbaumer, Florian Pfaff andFoot-and-mouth disease (FMD) is an acute, febrile, highly contagious disease of clovenhoofed animals caused by the foot-and-mouth disease virus (FMDV) [1]
We found that FMDV 3C generally decreased the protein levels of several host proteins involved in NF-κB signaling in a dose-dependent manner (Figures 1A–C and 2A–C)
We found that mutations in the catalytic triad of 3C (H46Y, D84N, or C163G) partly abolished the degradation of host proteins involved in NF-κB signaling (Figure 3A–C), indicating that the protease activity of FMDV 3C is involved in the degradation of these host proteins
Summary
Foot-and-mouth disease (FMD) is an acute, febrile, highly contagious disease of clovenhoofed animals caused by the foot-and-mouth disease virus (FMDV) [1]. The specific mechanisms of 3C-induced degradation of some proteins such as γ-tubulin, Karyopherin 1 (KPNA1), double-stranded RNA-activated protein kinase (PKR), and autophagy-related 5 homolog–12 homolog (ATG5–ATG12) are still unclear [12,13,14,15]. Upon external or intrinsic stimuli, apoptosis is induced by the activation of a death signal and utilizes a cascade of caspases. The activation of caspases or other proteases induces multiple cleavage events, subsequently causing apoptosis-associated morphological changes, including membrane blebbing, chromatin condensation and cell shrinkage [16,17]. The present study verified that FMDV 3C degrades multiple molecules involved in NF-κB signaling through its proteolytic activity. Further research found that apoptosis inducers caused the same molecules to degrade and an apoptosis inhibitor, CrmA restored the abundance of proteins degraded by 3C-expression, whereas the disruption of caspase, caspase, and caspase activity did not affect the degradation events. Our study reveals a critical role of 3C in degrading various molecules involved in NF-κB signaling and inducing apoptosis and confirms that an apoptosis inhibitor impedes the degradation induced by 3C
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