LY6E regulates Pseudorabies virus early infection via impairing viral internalization.

Pseudorabies virus (PRV) causes Aujeszky's disease, posing an emerging threat to the livestock industry and raising concern for human health. Host cells employ a wide range of intrinsic factors to combat viral infections; however, the host factors involved in restricting PRV entry remain poorly understood. In this study, using both human and porcine cell models, we identified a potent antiviral role of LY6E (lymphocyte antigen 6, family member E) in suppressing PRV infection. Overexpression of LY6E resulted in a significant reduction in PRV infection, whereas depletion of LY6E increased infection, supporting a promising antiviral role against PRV. Structure-function analyses identified that the proper structure of LY6E is indispensable for its full antiviral activity. Transcriptomic analysis revealed that LY6E modulates specific host signaling pathways during PRV infection without triggering global transcriptional alterations. Furthermore, LY6E was found to interact with PRV envelope glycoproteins, implying its role in regulating viral entry. Subsequent investigations revealed that LY6E does not interfere with the initial attachment of PRV to host cells but specifically impairs viral internalization. Collectively, this study identifies LY6E as a previously unrecognized host restriction factor for PRV and highlights the role of surface proteins in controling viral entry. Additionally, it broadens the antiviral spectrum of LY6E to DNA viruses, beyond its previously reported host-viral interaction in RNA viruses.