RNA‐Binding Protein RBM25 Targets the mRNA Stability of GTPase Rab22a to Restrict Viral Entry and Infection

Viral infections trigger complex host defense responses, yet many key regulatory mechanisms remain undefined. Here, we identify the RNA-binding protein RBM25 as a potent, broad-spectrum host antiviral factor, independently of the type I interferon (IFN-I) pathway. Viral infection downregulates RBM25 expression, and RBM25-deficient mice exhibit enhanced susceptibility to multiple viruses and more aggravated tissue damage. In vitro, RBM25 inhibits the viral infection and replication across a spectrum of RNA and DNA viruses. Mechanistically, the antiviral activity of RBM25 is independent of IFN-I signaling and is instead linked to an early blockade in the viral life cycle. RBM25 specifically impedes viral cell entry through the suppression of the host GTPase Rab22a, a well-known facilitator of viral endocytosis. Virus infection-elicited downregulation of RBM25 results in Rab22a upregulation, which consequently potentiates viral entry. Furthermore, we elucidate the post-transcriptional mechanisms that RBM25 interacts with RC3H1 (ring finger and CCCH-type domains 1) to form an RNA-binding complex that binds and destabilizes Rab22a mRNA, thereby limiting its protein translation. Collectively, our work unveils the RBM25/RC3H1-Rab22a axis as an interferon-independent post-transcriptional pathway that governs viral entry by modulating the mRNA stability of a critical host endocytosis factor, which presents a potential target for developing broad-spectrum antiviral strategies.