The E3 ubiquitin ligase STUB1 inhibits Senecavirus A replication by mediating VP1 ubiquitination and proteasomal degradation

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ABSTRACT Senecavirus A (SVA), an emerging vesicular pathogen, poses a significant threat to the global pig industry. STIP1 homology and U-box-containing protein 1 (STUB1), a chaperone-dependent E3 ubiquitin ligase, plays a pivotal role in protein quality control by mediating target protein degradation. However, its precise role of STUB1 in regulating SVA replication remains undefined. In this study, we combined liquid chromatography-mass spectrometry, confocal imaging, and Western blotting to demonstrate that STUB1 interacts with the SVA VP1 protein and negatively regulates SVA replication. Mechanistically, STUB1 promotes the ubiquitination-dependent degradation of VP1 by specifically targeting lysine residues at positions 177 and 260 (K177 and K260). This degradation process is significantly enhanced by heat shock protein 70 (HSP70) and heat shock cognate protein 70 (HSC70), which strengthen the STUB1-VP1 interaction. Notably, the SVA 3C protease (3Cpro) counteracts this antiviral defense by enzymatically reducing STUB1 expression. In vivo studies using a mouse model showed that a VP1 mutant virus lacking STUB1-targeted ubiquitination sites replicates more efficiently than the wild-type strain, resulting in significantly higher viral loads across multiple tissues and more severe pulmonary pathology. Together, these findings reveal that STUB1 inhibits SVA replication through ubiquitination-dependent degradation of VP1, a process that is antagonized by viral 3C protease via suppression of STUB1 expression. IMPORTANCE Viruses have evolved diverse strategies to enhance their replication efficiency. Senecavirus A (SVA), an emerging porcine pathogen associated with vesicular disease outbreaks, has become increasingly prevalent in swine populations worldwide. As a chaperone-dependent E3 ubiquitin ligase, STUB1 plays a crucial role in maintaining cellular protein homeostasis. In this study, we elucidated the functional interplay between STUB1 and SVA replication. Our results demonstrate that STUB1 directly interacts with the viral protein VP1 and mediates its ubiquitination-dependent degradation through specific targeting of lysine residues at positions 177 and 260 (K177 and K260), thereby significantly inhibiting viral replication. However, SVA has evolved a countermeasure, whereby its 3C protease (3Cpro) downregulates STUB1 expression, effectively blocking VP1 degradation and subverting this host antiviral defense to promote viral propagation. These findings not only reveal novel host-virus interaction mechanisms but also provide valuable molecular targets for developing innovative strategies to control SVA infection.

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