Lumpy skin disease virus protein LSDV122 impairs IFN-I receptor complex formation to evade host innate immunity.

Lumpy skin disease virus (LSDV) is a pathogenic poxvirus that causes systemic disease in cattle. Although LSDV encodes multiple proteins that are predicted to regulate host defense, the underlying mechanisms of its immune evasion strategies remain largely elusive. Here we identify the LSDV-encoded protein LSDV122 as an antagonist of type I interferon (IFN-I)-mediated innate immunity. LSDV122 interacts with both subunits of the IFN-I receptor, IFNAR1 and IFNAR2, disrupting their proper assembly and preventing the recruitment of the downstream kinases JAK1 and TYK2, leading to impairment of IFN-β-mediated JAK-STAT signaling and induction of antiviral IFN-stimulated genes (ISGs). Deletion of the LSDV122 gene (LSDVΔ122) led to stronger antiviral response by restoring IFN-β-induced signaling in vitro and in a mouse model. Our study suggests that LSDV122 plays a critical role in antagonizing IFN-I signaling and is essential for efficient viral immune evasion, offering new insights into the rational design of live-attenuated LSDV vaccines.