Seneca Valley virus 3C protease targets TRIM32 for cleavage to antagonize its antiviral effects

The Seneca Valley virus (SVV), a newly emerged virus within the Picornaviridae family, causes porcine idiopathic vesicular disease, imposing substantial economic costs to the global pork industry. However, the molecular mechanisms underlying its pathogenesis remain poorly understood. In this study, we identified TRIM32 as a novel antiviral factor against SVV and found that SVV infection led to the cleavage and degradation of TRIM32. Knocking down TRIM32 increased viral replication, while overexpressing it reduced viral titers. Further study showed that TRIM32 restricts SVV replication by selectively targeting viral VP3 protein for ubiquitination and proteasomal degradation. To counteract this, SVV 3C protease (3Cpro) targets TRIM32 for cleavage at E332. This cleavage renders TRIM32 unable to inhibit SVV replication or block the degradation of VP3. Additionally, the cleaved TRIM32 products weaken E3 ubiquitin ligase activity and reduce activation of the type I interferon (IFN) pathway. Taken together, our results indicate that SVV 3C^pro-mediated cleavage of TRIM32 impairs its function in the ubiquitination and degradation of viral VP3 and type I IFN signaling. These findings offer novel insights into the strategies viruses use to evade the host's antiviral immune responses, thereby contributing to efficient viral replication.

Seneca Valley virus (SVV) is an emerging pathogen that causes vesicular diseases in pigs, posing a significant threat to the global swine industry. Tripartite motif-containing protein (TRIM) family members are recognized as intrinsic antiviral effectors that provide a frontline shield against viruses prior to the transcription of interferon (IFN) and interferon-stimulated genes (ISGs). In this study, we uncovered the antiviral mechanism, which promotes the K48-linked ubiquitination of viral VP3 protein, leading to the degradation of VP3 via the proteasome pathway. SVV 3C^pro abolished the antiviral effects of TRIM32 by inducing its cleavage. The cleaved TRIM32 fragment attenuates its E3 ubiquitin ligase activity and weakens the activation of IFN signaling. Our results reveal a potential mechanism of viral immune evasion, which is crucial for understanding how SVV has evolved a novel strategy to evade the intrinsic cellular restrictions against viral infection.