Trim25 restricts rabies virus replication by destabilizing phosphoprotein

Tripartite motif-containing protein 25 (Trim25) is an E3 ubiquitin ligase that activates retinoid acid-inducible gene I (RIG-I) and promotes the antiviral interferon response. Recent studies have shown that Trim25 can bind and degrade viral proteins, suggesting a different mechanism of Trim25 on its antiviral effects. In this study, Trim25 expression was upregulated in cells and mouse brains after rabies virus (RABV) infection. Moreover, expression of Trim25 limited RABV replication in cultured cells. Overexpression of Trim25 caused attenuated viral pathogenicity in a mouse model that was intramuscularly injected with RABV. Further experiments confirmed that Trim25 inhibited RABV replication via two different mechanisms: an E3 ubiquitin ligase-dependent mechanism and an E3 ubiquitin ligase-independent mechanism. Specifically, the CCD domain of Trim25 interacted with RABV phosphoprotein (RABV-P) at amino acid (AA) position at 72 and impaired the stability of RABV-P via complete autophagy. This study reveals a novel mechanism by which Trim25 restricts RABV replication by destabilizing RABV-P, which is independent of its E3 ubiquitin ligase activity.