Prkra is the double-stranded RNA sensor to mediate an embryonic integrated stress response

Abstract Nucleic acid sensing, the initial stage of pathogen detection, plays a fundamental role in innate immunity. Double-stranded RNAs, mainly of viral origin, are recognized by protein kinase R (PKR/Eif2ak2) in differentiated cells to trigger an integrated stress response (ISR), characterized by the inhibition of global translation. However, in pluripotent cells, the sensor of double-stranded RNAs in antiviral innate immunity is poorly defined and conflated with those in differentiated cells. In this study, we utilized early zebrafish embryos as a model for pluripotent cells and discovered that dsRNA stimulation induces cell necrosis and a PKR-independent blockage of translation initiation. We identified Prkra as the genuine dsRNA sensor in this unique embryonic ISR. Prkra binds to and polymerizes on dsRNAs, diverting the eIF2 complex away from the translation machinery. Consequently, the formation of the 43S preinitiation complex is significantly reduced, leading to a hindrance in global protein synthesis. This distinctive embryonic ISR not only restricts RNA virus SVCV replication in zebrafish embryos but also exhibits conservation in early mouse embryos and embryonic stem cells. Therefore, the Prkra-mediated translation blockage potentially represents a common antiviral strategy across species. Graphical abstract