Detection of exogenous RNA by cellular helicases represents a cornerstone of the innate immune system. The prototypical RIG-I-like receptors make evolutionarily conserved partnerships with E3 ubiquitin ligases, the latter building polyubiquitin tethers that facilitate receptor/adapter clustering and antiviral signal amplification.  Here we identify a unique and parallel system comprising an RNA helicase, ZNFX1, with intrinsic ubiquitin ligase activity. We find that ZNFX1 restricts Sindbis virus in an RNA and ubiquitin ligase-dependent manner. We demonstrate that a key component of the restriction is silencing of the viral RNA in ZNFX1 aggregates shortly following infection. Furthermore, children born with mutations in ZNFX1 suffer acute viral infections and hemophagocytic lymphohistiocystosis-like disease, an immunodeficiency resulting in multi-organ failure. We show that these mutations render ZNFX1 unable to control virus replication, suggesting quarantining of viral RNA represents an overlooked yet significant feature of innate immunity.