SUMOylation and ubiquitination reciprocally regulate SMCHD1 antiviral activity against herpes simplex virus 1.

Host restriction factors serve as intrinsic barriers against viral infection, and are frequently counteracted by viral antagonists. Previous studies, including our own, have identified SMCHD1 as a restriction factor that suppresses the replication of multiple viruses. Here, we reveal that the antiviral activity of SMCHD1 is dynamically regulated by two different post-translational modifications. SUMOylation of SMCHD1 promotes its association with the viral genome and enhances its antiviral activity. In contrast, during herpes simplex virus 1 (HSV-1) infection, the viral E3 ligase ICP0 induces SMCHD1 ubiquitination and proteasomal degradation, thereby relieving viral restriction. Loss of ICP0 stabilizes SMCHD1 and leads to marked accumulation of SUMOylated SMCHD1, rendering ICP0-deficient HSV-1 more sensitive to SMCHD1-mediated inhibition. Together, our findings uncover a reciprocal SUMO-ubiquitin regulatory mechanism that governs SMCHD1 antiviral activity and highlight a refined virus-host arms race centered on biphasic modification of a single restriction factor.