The La Region of Foot-and-Mouth Disease Virus: Essential for L Protein Cellular Distribution but Not Functional Activity

Foot-and-mouth disease virus (FMDV) is a highly contagious picornavirus that affects cloven-hoofed animals and carries significant economic implications for the global livestock industry. FMDV features two Leader (L) protein isoforms, Lab and Lb, differing at their amino termini by 28 amino acids (La region). Currently, the activity of La protein sequences has not been investigated. To address this issue, the comparison study of biological and functional roles of Lab and Lb was performed as the La region alone did not independently perform protein function. We found that Lab and Lb significantly regulated FMDV replication and pathogenicity, and their coexistence afforded optimal FMDV properties. Subsequently, we observed that both L isoforms cleaved eukaryotic translation initiation factor 4G (eIF4G) I, suppressed type I and type III interferon (IFN) expression, and exhibited marked cytotoxicity, indicating that they were all key components in FMDV's antagonism of host antiviral defenses. Finally, the subcellular distribution of Lab and Lb was detected. Despite dual localization in cytoplasmic and nuclear compartments, both isoforms displayed different spatial distribution patterns, and Lb induced more pronounced morphological changes to host cells than Lab. Furthermore, bioinformatics predicted that the La region might contain a non-classical secretory signal peptide, potentially facilitating Lab distribution to the cell membrane or extracellular space. Collectively, the primary encoding role of La region was to control the intracellular distribution of L protein, as opposed to regulating its functional activity. This study may help to deepen our understanding of why FMDV encoded two isoforms of L protein.