GRWD1 enhances HSV-1 replication by facilitating nuclear egress.

Herpes simplex virus 1 (HSV-1) depends on host factors for its replication. Here, we identify glutamate-rich WD40 repeat-containing 1 (GRWD1) as a novel pro-viral host factor that facilitates HSV-1 nuclear egress. GRWD1 knockdown trapped nucleocapsids in the nucleus and suppressed viral replication. This function appears to require the viral kinase US3, as GRWD1's effect was abolished in US3-deficient infections. We further show that GRWD1 interacts with US3 and partially colocalizes with the viral nuclear egress complex protein UL34 at the nuclear membrane in both HSV-1-infected and HSV-1ΔUS3-infected cells. Mechanistically, GRWD1 promotes the proteasomal degradation of Lamin A/C and directly binds Lamin A, suggesting a model where it disrupts the nuclear lamina to facilitate capsid exit. Our findings reveal a novel virus-host interaction that promotes HSV-1 nuclear egress. IMPORTANCE: Alphaherpesviruses, including herpes simplex virus 1 (HSV-1), cause lifelong infections and severe diseases globally by subverting host machinery for replication. Using HSV-1 as a model, we identified glutamate-rich WD40 repeat-containing 1 (GRWD1) as a critical host factor enabling viral nuclear egress, a key step in viral propagation. GRWD1 facilitates nuclear escape of capsids via degradation of Lamin A/C and directly interacts with Lamin A. These findings reveal a novel mechanism by which HSV-1 exploits GRWD1 to breach nuclear barriers, highlighting GRWD1 as a potential target for disrupting herpesvirus replication and developing broad-spectrum antivirals.