The herpesvirus UL49.5 protein hijacks a cellular C-degron pathway to drive TAP transporter degradation.

Herpesviruses are masters of immune evasion. Most often, they hijack host cellular pathways to modulate the antiviral immune response. Varicellovirus UL49.5 orthologs have evolved as inhibitors of the transporter associated with antigen processing (TAP) and, this way, major modulators of the MHC class I-restricted antigen presentation. This study identifies the long-sought molecular mechanism exploited by bovine herpesvirus 1-encoded UL49.5 to trigger proteasomal degradation of TAP. Our findings demonstrate that the viral protein hijacks host cell CRL2-ubiquitin conjugation and ER-associated degradation pathways to promote TAP degradation. These findings advance the understanding of how herpesviruses can manipulate the cellular machinery.