ACBD3 promotes the antiviral innate immune response against vesicular stomatitis virus infection by stabilizing MAVS through TRIM21

Acyl-CoA binding domain containing protein 3 (ACBD3) is a Golgi protein implicated in multiple cellular processes. However, its function in negative-strand RNA virus infection and innate immune responses remains poorly understood. Here, we identify ACBD3 as a novel positive regulator of host defense that potently inhibits vesicular stomatitis virus (VSV) replication in HeLa cells with ACBD3 overexpression or knockdown. Mechanistically, our investigation unveils a previously unknown ACBD3-TRIM21-MAVS axis. Co-immunoprecipitation combined with mass spectrometry analysis reveals that ACBD3 interacts with the E3 ubiquitin ligase TRIM21, and this interaction is crucial for stabilizing the mitochondrial antiviral-signaling protein (MAVS). During VSV infection, ACBD3 enhances TRIM21 protein levels, thereby promoting MAVS accumulation and facilitating the activation of type I interferon signaling. Collectively, our findings elucidate a novel mechanism by which ACBD3 sustains innate immunity via TRIM21 to restrict VSV replication, providing a potential therapeutic target and strategy for combating negative-strand RNA viruses.