Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

During viral infection, several dsRNA sensors are activated in the cell and trigger signaling that leads to changes in gene expression. One of these sensors activates an endonuclease, RNase L, that cleaves many types of RNA in the cell. However, how the resultant widespread RNA decay affects gene expression is not fully understood. Here we found that gene expression changes caused by activating dsRNA sensing pathways are tuned by RNase L activation, pointing to intricacy in the innate immune response where multiple inputs are integrated to create an optimized output. We show that RNase-L-dependent RNA fragmentation induces the activation of the Ribotoxic Stress Response, potentially through ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L appears to limit the translation of genes that are regulated by another dsRNA-induced pathway, the Integrated Stress Response. Intriguingly, we found the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage events can directly evoke an antiviral program. Key summary ### Competing Interest Statement The authors have declared no competing interest.