Structural insights into the nuclear import of haliotid herpesvirus 1 large tegument protein homologue

Abalone are highly susceptible to haliotid herpesvirus 1 (HaHV1), the causative agent of abalone viral ganglioneuritis (AVG), a re-emerging disease responsible for significant mortality events in both wild and farmed populations. Currently, there are no effective antiviral treatments or preventive measures available against HaHV1, which is partly due to the limited understanding of the immune responses and viral pathogenesis in this non-model marine invertebrate. This highlights the urgent need for novel intervention strategies, including investigations into the molecular mechanisms underlying HaHV1 infection. In other herpesviruses, the large tegument protein UL36 plays a crucial role in transporting the viral capsid to the host cell’s nuclear pore complex (NPC), mediated by N-terminal nuclear localization signals (NLSs). However, the nuclear import mechanism of UL36 homologue (UL36h) in HaHV1 remains largely uncharacterized. In this study, we identified and functionally characterized the NLS motif within HaHV1 UL36h and elucidated its interactions with the importin alpha (IMPα) nuclear import receptor. Through a combination of high-resolution crystallography and quantitative binding assays, we determined the key residues responsible for binding to IMPα and demonstrated isoform-specific variations in binding affinity. Our biochemical and structural analyses confirmed key interactions within the NLS that are essential for IMPα interactions. These findings advance our molecular understanding of HaHV1 host interactions and pave the way for the development of targeted antiviral strategies against abalone herpesvirus infection.