FUS/TLS suppresses enterovirus replication and promotes antiviral innate immune responses.

During viral infection, the dynamic virus-host relationship is constantly in play. Many cellular proteins such as RNA-binding proteins (RBPs) have been shown to mediate antiviral responses during viral infection. Here we reported that the RBP, fused in sarcoma/translocated in liposarcoma (FUS/TLS), acts as a host restricting factor against the infection of coxsackievirus B3 (CVB3). Mechanistically, we found that deletion of FUS leads to increased viral RNA transcription and enhanced internal ribosome entry site (IRES)-driven translation, with no apparent impact on viral RNA stability. We further demonstrated that FUS physically interacts with viral genome, which may contribute to direct inhibition of viral RNA transcription/translation. Moreover, we identified a novel function for FUS in regulating host innate immune response. We showed that in the absence of FUS, gene expression of type I interferons and proinflammatory cytokines elicited by viral or bacterial infection is significantly impaired. Emerging evidence suggests a role for stress granules (SGs) in antiviral innate immunity. We further uncovered that knockout of FUS abolishes the ability to form SGs upon CVB3 infection or polyinosinic:polycytidylic acid (polyIC) treatment. Finally, we showed that, to avoid FUS-mediated antiviral response and innate immunity, CVB3 infection results in cytoplasmic mislocalization and cleavage of FUS through the enzymatic activity of viral proteases. Together, our findings in this study identified FUS as a novel host antiviral factor, which restricts CVB3 replication through direct inhibition of viral RNA transcription and protein translation and by regulating host antiviral innate immunity.IMPORTANCEEnteroviruses are common human pathogens, including those that cause myocarditis (coxsackievirus B3, CVB3), poliomyelitis (poliovirus) and hand, foot and mouse disease (enterovirus 71). Understanding the virus-host interaction is crucial for finding the treatment and prevention of these pathogens. In this study, we explored the interplay between host RNA binding protein FUS/TLS and CVB3 and reported that FUS/TLS restricts CVB3 replication through direct inhibition of viral RNA transcription/translation and by regulation of cellular antiviral innate immunity. To impede the antiviral role of FUS, CVB3 targets FUS for mislocalization and cleavage. Findings from this study provide novel insights into interactions between CVB3 and the FUS, which may lead to novel therapeutic interventions against enterovirus-induced diseases.