Alphavirus infection triggers selective cytoplasmic translocation of nuclear RBPs with moonlighting antiviral roles.

RNA is a central molecule for viruses; however, the interactions that viral RNA (vRNA) establishes with the host cell is only starting to be elucidated. Here, we determine the ribonucleoprotein (RNP) composition of the prototypical arthropod-borne Sindbis virus (SINV). We show that SINV RNAs engage with hundreds of cellular proteins, including a group of nuclear RNA-binding proteins (RBPs) with unknown roles in infection. We demonstrate that these nuclear RBPs are selectively translocated to the cytoplasm after infection, where they accumulate in the viral replication organelles (ROs). These nuclear RBPs strongly suppress viral gene expression, with activities spanning viral species and families. Particularly, the U2 small nuclear RNP (snRNP) emerges as an antiviral complex, with both its U2 small nuclear RNA (snRNA) and protein components contributing to the recognition of the vRNA and the antiviral phenotype. These results suggest that the U2 snRNP has RNA-driven antiviral activity in a mechanism reminiscent of the RNAi pathway.