DDX3X suppresses RIG-I dependent type I Interferon production and promotes Mammarenavirus growth.  

Host RNA helicases regulate replication, transcription and translation of RNA viruses. Given such dependency, host organisms may have evolved a viral sensing mechanism that links RNA helicase perturbation with innate responses. Our lab identified the host DEAD-box ATP-dependent-RNA-helicase 3 (DDX3X) is necessary for viral replication but also suppresses Type I interferon (IFN-I) responses during Mammarenaviruses (MA) infection in immortalized cell lines. These findings extended to mice with DDX3X deficiency in Dendritic Cells as well as DDX3X-deficient human primary fibroblasts infected with MA. Remarkably, we observed increased IFN-I when DDX3X-deficient fibroblasts were stimulated with RIG-I agonists, supporting DDX3X’s role as a general IFN-I suppressor. Finally, analysis of fibroblasts from patients with DDX3X Syndrome (DDX3X-S) revealed that the Q417P mutation heightened IFN-I signature after MA infection, but did not affect MA replication, demonstrating that DDX3X pro-viral and IFN-I-antagonistic activities are dissociated. Our results reveal DDX3X is necessary for both MA replication and IFN-I suppression. This dual role may allow initiation of innate responses when DDX3X is sequestered by a replicating virus, suggesting a previously unrecognized general strategy for detecting RNA virus infections that rely on host helicases. In addition, our data from individuals with DDX3X-S raise the possibility that patient symptoms may be aggravated by enhanced IFN-I responses.