Viperin weakens IFN-I-induced immune activity by facilitating STAT1 degradation through E3 ligase UBE4A

Viperin is considered as an antiviral protein known to directly target a variety of viruses. However, whether and how Viperin affects virus infection by targeting intracellular immune signaling remain unexplored. Here, we reveal that Viperin inhibits type-I interferon (IFN-I) antiviral immune signaling by degrading STAT1. We found that IFN-I upregulates the ubiquitin E3 ligase ITCH to degrade UBR5, while Viperin subsequently recruit another ubiquitin E3 ligase UBE4A to promote STAT1 ubiquitination and degradation to attenuate IFN-I signaling. Moreover, the multifunctional interfering peptide VS-IP1 can block Viperin-mediated STAT1 degradation, thus enhancing IFN-I antiviral immune function. This study reveals that Viperin is a suppressor of IFN-I immune signaling, which could renew understanding of the biological function of Viperin, and provide a strategy for enhancing clinical IFN-I therapeutic efficacy. • Viperin inhibits IFN-I signaling by promoting STAT1 degradation. • IFN-I-induced STAT1 degradation by Viperin is UBR5-independent, distinct from CVB3 infection. • IFN-I upregulates ITCH to degrade UBR5, enabling Viperin to recruit UBE4A for STAT1 ubiquitination. • VS-IP1 peptide blocks Viperin-STAT1 interaction and enhances IFN-I antiviral efficacy.