An interferon independent innate immune response to double stranded RNA in embryonic stem cells

In vertebrate early embryos and embryonic stem cells, the interferon (IFN)-centered double-stranded RNA (dsRNA) sensing and signaling pathway is markedly suppressed, implying the existence of an alternative repertoire of dsRNA sensors in these stages. We recently reported that dsRNA treatment triggers translation inhibition using Prkra as a sensor in zebrafish and mouse early embryos. Independently, here we show that dsRNA stimulates the expression of a subset of interferon-stimulated genes (ISGs) in the absence of IFN production, establishing a defensive state in mouse embryonic stem cells (mESCs). Upon dsRNA stimulation, the multifunctional DExD/H-box RNA helicase Dhx9 is recruited into dsRNA-induced condensates, where it promotes the recruitment and functional suppression of the Mdm2/Cul4A ubiquitin ligase machinery by excluding their substrate adaptor Ddb1, thereby stabilizing p53 and Stat1. Dhx9, p53 and Stat1 then cooperate to stimulate an ISG response. This signaling is important for the defense against ZIKV infection in mESCs as well as other dsRNA stresses. Such a cascade is conserved in human ESCs, while in zebrafish embryos, p53 but not Stat1 is required for the transcriptional response. Our findings define an immediate, cell-autonomous innate immune pathway operating in ESCs and vertebrate embryos.