Pseudorabies Virus UL41 Hijacks IFN Response via JAK/STAT Pathway While Cellular TRIM21 Blocks it Through K48 Ubiquitination.

Pseudorabies virus (PRV), a significant pathogen that infects various animals, including pigs, encodes multiple proteins that participate in host-pathogen interactions. This study investigates the mechanisms by which PRV evades host immune responses, with a particular focus on the role of the UL41 protein and its interactions with host factors. We found that PRV infection modulates the interferon (IFN) signaling pathway, suppressing the expression of IFN-β and downstream antiviral factors while upregulating IFN-α. However, the direct role of UL41 in IFN-α upregulation remains to be elucidated. The PRV UL41 protein was shown to directly target the JAK/STAT pathway, binding to specific motifs, such as the conserved sequences KUUUCY and CSDGGA, in the untranslated region (UTR) of key mRNAs and degrading them, thereby inhibiting IFN-I signal transduction. Simultaneously, the UL41 can interact with host proteins, such as poly(A) binding protein (PABPC1) and host restriction factor tripartite motif protein 21 (TRIM21). Additionally, we discovered an antagonistic relationship between PRV UL41 and TRIM21. TRIM21, acting as an E3 ubiquitin ligase, binds to UL41 through its SPRY/PRY domain and mediates the degradation of the protein via the K48-ubiquitin-proteasome pathway. This interaction modulates the JAK/STAT pathway, with TRIM21 counteracting the inhibitory effect of UL41. In addition, the residue F78 within PRV UL41 is crucial for modulating mRNA and protein binding and ribonuclease (RNase) function, facilitating interactions with target proteins such as PABPC1 and TRIM21, and inhibiting the JAK/STAT pathway. These findings enhance our understanding of PRV pathogenesis and provide potential targets for developing novel antiviral strategies.