African swine fever virus pM448R protein promotes STUB1-mediated ubiquitin-proteasome degradation of IRF1 to attenuate type III interferon induction.

African swine fever virus (ASFV) primarily invades through the respiratory and intestinal mucosa, where type III interferons (IFN-λ) play a pivotal role in local immunity. However, whether ASFV counteracts this IFN-λ-mediated antiviral defense remains largely unknown. Here, we demonstrate that ASFV infection dampens IFN-λ production, where the viral protein pM448R serves as a suppressor. Mechanistically, pM448R targets interferon regulatory factor 1 (IRF1) for proteasomal degradation by recruiting the E3 ubiquitin ligase STIP1 homology and U box-containing protein 1 (STUB1), which catalyzes K48-linked ubiquitination of IRF1. Moreover, infection with the M448R-deficient ASFV mutant leads to increased IRF1 protein stability and elevated expression of IRF1 target genes, including OAS1, OAS2, and ZBP1. Our findings reveal a novel immune evasion strategy whereby ASFV hijacks the host ubiquitin-proteasome system to degrade IRF1, thereby subverting IRF1-dependent transcriptional programs, including IFN-λ induction, to facilitate mucosal invasion.IMPORTANCEAfrican swine fever virus (ASFV) remains a major threat to the global swine industry. However, how the virus evades mucosal innate immunity at its portal of entry remains poorly understood. The transcription factor IRF1 serves as a central hub in mucosal antiviral defense, coordinating the expression of IFN-λ and numerous other restriction factors. In this study, we identify pM448R as a viral antagonist that directs IRF1 for ubiquitin-mediated degradation, which reveals a novel mechanism by which ASFV destroys the mucosal immune barrier. These findings not only deepen our understanding of viral interference with IRF1-dependent defense pathways, but also provide potential insights for the development of live-attenuated vaccines.