Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response

Viral and endogenous double-stranded RNA (dsRNA) is a potent trigger for programmed RNA degradation by the 2-5A/RNase L complex in cells of all mammals. This 2-5A-mediated decay (2-5AMD) is a conserved stress response switching global protein synthesis from homeostasis to production of interferons (IFNs). To understand this mechanism, we examined 2-5AMD in human cells and found that it triggers polysome collapse characteristic of inhibited translation initiation. We determined that translation initiation complexes and ribosomes purified from translation-arrested cells remain functional. However, spike-in RNA sequencing (RNA-seq) revealed cell-wide decay of basal mRNAs accompanied by rapid accumulation of mRNAs encoding innate immune proteins. Our data attribute this 2-5AMD evasion to better stability of defense mRNAs and positive feedback in the IFN response amplified by RNase L-resistant molecules. We conclude that 2-5AMD and transcription act in concert to refill mammalian cells with defense mRNAs, thereby “prioritizing” the synthesis of innate immune proteins. [Display omitted] •DsRNA rapidly arrests translation using 2-5A/RNase-L-mediated mRNA decay•Defense mRNAs preferentially accumulate due to positive feedback in the IFN response•RNase L-cleaved ribosomes are translationally competent•Human cells have RNase-L-inaccessible poly(A)+ mRNA pools that are not translating Rath, Prangley, et al. report that human cells reprioritize translation via cell-wide mRNA destruction in response to double-stranded RNA (dsRNA), a potent immunogenic signal. While all mRNAs are attacked, critical interferon (IFN) and defense mRNAs escape depletion via a kinetic mechanism arising from transcription with positive feedback.