TRIM21 inhibited PRV infection and downregulated IFN-α, IL-6, and TNF-α during the infection.

Pseudorabies virus (PRV) is a neurotropic alphaherpesvirus that establishes a latent infection in the peripheral nervous system of swine, causing severe economic losses in the global pig industry. Although conventional vaccines effectively control classical PRV strains, emerging recombinant variants frequently evade vaccine-mediated immunity, causing recurrent outbreaks. In this study, we investigated the regulatory roles of tripartite motif-containing protein 21 (TRIM21) in PRV replication, interferon production, and proinflammatory cytokine expression. Our results demonstrated that TRIM21 expression negatively correlated with PRV replication, and its RING and PRY/SPRY domains were indispensable for antiviral activity. Mechanistically, TRIM21 targeted PRV immediate-early protein 180 (IE180), the sole immediate-early gene product of PRV, via its RING and PRY/SPRY domains to degrade the viral protein and thus regulate viral transcriptional activation. Moreover, TRIM21 downregulated IFN-α expression through the RING and PRY/SPRY domains, and inhibited IL-6 and TNF-α production mainly via the PRY/SPRY domain. Collectively, these findings revealed that TRIM21 acts as a double-edged sword during PRV infection: it restricted PRV replication by degrading IE180 while dampening host antiviral interferon and proinflammatory responses.