RNase L regulates the antiviral proteome by accelerating mRNA decay, inhibiting nuclear mRNA export, and repressing...

Ribonuclease L (RNase L) is an antiviral endoribonuclease that triggers widespread degradation of cellular mRNAs. Here, we show that RNase L-mediated decay of cellular mRNA is a conserved response to flaviviruses, including Zika virus (ZIKV), dengue virus serotype 2 (DENV-2), and West Nile virus (WNV). Quantitative mass spectrometry shows that RNase L downregulates proteins with short half-lives involved in cell-cycle progression, cellular metabolism, and protein synthesis. However, mRNAs encoding antiviral proteins that are induced by interferon-stimulated genes (ISGs) initially evade degradation by RNase L, allowing for the synthesis of critical antiviral proteins. At later times during the antiviral response, RNase L dampens ISG protein synthesis by triggering a block in nuclear mRNA export and repressing transcription. These findings show that RNase L regulates the antiviral proteome through an intricate balance of mRNA decay and nuclear RNA biogenesis, which is crucial for preventing overproduction of pro-inflammatory proteins.