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

Abstract

Viral 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 ZAK, 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 antiviral IFIT mRNAs and GADD34 that 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. HighlightsO_LIActivated RNase L acts with dsRNA-sensing pathways to promote cell signaling C_LIO_LIRNA fragmentation induces transcription through ZAK signaling C_LIO_LIActivation of RNase L modulates levels of eIF2 phosphorylation C_LIO_LITranslation of the GADD34 and IFIT mRNAs is inhibited by active RNase L C_LI