SUMOylation and ubiquitination of Viperin dynamically regulate the type I interferon-mediated antiviral response

Viperin is a broad-spectrum antiviral protein induced by interferon. Viperin in epithelial cells is regulated and degraded by E3 ubiquitin ligase UBE4A. Here, we observed that UBE4A expression was deficient in immune cells such as splenocytes and macrophages, and elucidated how the protein stability and antiviral activity of Viperin are regulated under the condition of UBE4A deficiency. Specifically, PJA2 mediates K48-linked polyubiquitination of Viperin at K358, leading to proteasomal degradation and enhanced viral susceptibility. Upon viral infection, host upregulation of RANBP2 enhances Viperin SUMO3-ylation, which competitively inhibits ubiquitination, thereby stabilizing Viperin and suppressing viral replication. However, prolonged infection recruits SENP1, causing deSUMOylation that promotes Viperin degradation and facilitates immune evasion. Viperin SUMOylation is modulated by small-molecule inhibitors such as Momordin-Ic and SENP1-IN-1. This study reveals a synergistic antiviral mechanism mediated by Viperin ubiquitination and SUMOylation, and further deepen the understanding of the protein homeostasis of Viperin and its role in the antiviral immune response.