Lumpy skin disease virus LSDV087 positively regulates innate immune response by promoting oligomerization of MITA/STING

Lumpy skin disease (LSD), caused by the lumpy skin disease virus (LSDV), is a contagious disease in cattle that poses a major threat to the global cattle industry. The functions of most LSDV-encoded proteins remain poorly characterized, particularly regarding their roles in regulating innate immunity. In this study, we show that the LSDV-encoded protein LSDV087 positively regulates innate immune response independently of its decapping enzymatic activity. LSDV087 interacts with the adaptor protein MITA (also called STING) in the innate immune pathway, inhibits its degradation by reducing K48-linked polyubiquitination, and promotes its oligomerization and subsequent activation of downstream signaling events, leading to enhanced innate immune response. Consistently, LSDV087-deficient virus (LSDV∆087) exhibits an attenuated ability to activate cGAS-MITA-mediated innate immune response. Collectively, our study reveals regulatory mechanisms of LSDV-triggered innate immune response and points to the possibility of targeting LSDV087 for rational design of live-attenuated LSDV vaccines.IMPORTANCELumpy skin disease virus (LSDV), which causes a contagious disease in cattle, poses a significant threat to the global cattle industry. Despite its impact, the functions of most LSDV-encoded proteins remain poorly understood. In this study, we report that LSDV087 plays dual roles in both promoting the cGAS-MITA-mediated innate immune response and downregulating host gene transcription. LSDV087 interacts with the adaptor protein MITA in the innate immune pathway, inhibits its degradation by reducing K48-linked polyubiquitination, and promotes its oligomerization, leading to the subsequent activation of downstream signaling events and an enhanced innate immune response. Additionally, as an immediate-early protein, LSDV087 functions as a decapping enzyme, preferentially targeting host transcripts with multiple exons to facilitate viral replication. This dual functionality underscores the complex interplay between LSDV immune evasion strategies and host defense mechanisms and may inform the rational design of live-attenuated LSDV vaccines.