Prkra dimer senses double-stranded RNAs to dictate global translation efficiency

Double-stranded RNAs (dsRNAs), known as conserved pathogen-associated molecular patterns, activate the integrated stress response via interferon-induced protein kinase R (PKR), leading to global translation inhibition. However, the interferon system is inactive in pluripotent cells, leaving the mechanisms of dsRNA sensing and translational control unclear. In this study, we utilized early zebrafish embryos as a model of pluripotent cells and discovered a PKR-independent blockage of translation initiation by dsRNA stimulation. Prkra dimer was identified as the genuine dsRNA sensor. Upon dsRNA binding, the dimerized dsRNA binding domain 3 of Prkra becomes activated to sequester the eIF2 complexes from the translation machinery, inhibiting global protein synthesis. This distinctive embryonic stress response restricts RNA virus replication in zebrafish embryos, is conserved in mouse embryonic stem cells, and compensates PKR function in differentiated cells. Therefore, the Prkra-mediated dsRNA sensing and translation control may serve as a common strategy for cells to adapt environmental stresses.