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

Abstract

SummaryViral infection triggers several dsRNA sensors that lead to changes in gene expression in the cell. One of these sensors activates an endonuclease, RNase L, that cleaves single stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here we show that this fragmentation induces the Ribotoxic Stress Response via ZAKα, 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 limits the translation of stress-responsive genes, including antiviralIFITmRNAs andGADD34that encodes an antagonist of 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 can evoke an antiviral program.HighlightsActivated RNase L acts with dsRNA-sensing pathways to promote cell signalingRNA fragmentation induces transcription through ZAKα signalingActivation of RNase L modulates levels of eIF2α phosphorylationTranslation of theGADD34andIFITmRNAs is inhibited by active RNase L