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Discs large membrane-associated guanylate kinase (MAGUK) scaffold protein 1 (DLG1) plays important roles in cell contact and migration, but its role in antiviral innate immunity is not clear. In this study, the role of DLG1 in the antiviral innate immune response and its impact on type-I interferon (IFN-I) signaling were investigated. DLG1 plays a critical role in promoting the IFN-I response by inhibiting the autophagic degradation of the innate immune adaptor IκB kinase epsilon (IKKε). As a result, DLG1 effectively suppresses negative-stranded RNA virus replication, including that of viruses such as vesicular stomatitis virus, Sendai virus, and bovine ephemeral fever virus. DLG1 was found to enhance the production of IFN-β and IFN-stimulated genes, leading to the attenuation of virus propagation. Mechanistically, DLG1 competitively binds to the E3 ubiquitin ligase March2, preventing the ubiquitination and subsequent degradation of IKKε. Notably, March2 specifically catalyzes K27-linked polyubiquitination of IKKε. The interaction between March2 and IKKε is mediated by the transmembrane domain of March2 and the C-terminal domain of IKKε. Furthermore, p62 acts as a cargo receptor, recognizing ubiquitinated IKKε for eventual autophagic degradation, whereas the process is blocked by DLG1. Additionally, the results demonstrated a significant decrease in DLG1 mRNA and protein levels upon negative-stranded RNA virus infection. Overall, these findings provide insights into the molecular mechanisms by which DLG1 promotes IFN-I production by regulating IKKε expression to inhibit viral replication. [ABSTRACT FROM AUTHOR]