Double-stranded RNA triggers a distinct integrated stress response in the early embryo [RNA-seq, Ribo-seq]

Double-stranded RNA (dsRNA) is associated with virus infections and is present as by-products during the transcription of synthetic mRNA, which has been widely used in gene gain-of-function studies and serves as a core component in emerging mRNA-based therapies1-4. The presence of dsRNA in host cells induces an integrated stress response that functions to prevent virus replication and infection5,6. Unlike differentiated cells, undifferentiated cells adopt a distinct defense strategy against RNA virus infection7, but the mechanism is unclear. We show a previously unidentified response triggered by dsRNA in the early embryo. Although dsRNA causes a global protein translation inhibition in a PKR-eIF2a independent manner and leads to developmental delay and cell necrosis, it also strongly induces p53 activation, which then upregulates Interferon Stimulated Genes independently of interferon ligands. Importantly, we demonstrate that the burst of p53 signaling dose not result in cell death but functions as a protective mechanism against deleterious translation blockage by slowing down global protein degradation via ISGylation. Our work has identified a distinct dsRNA-induced stress response in the embryo, reflecting an ancient innate immune memory before the establishment of the IFN system. It also raises the provocative question as to the original protective role of p53 during evolution. Overall design: To characterize the distribution of ribosomes on mRNA, we performed Ribosome profiling (Ribo-seq) analysis with RNA-seq on dsRNA-injected embryos.