Abstract
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.
Highlights
The innate immune system is activated rapidly without a delay for antibody production
The innate immune system relies on interferon (IFN) signaling coupled with a vertebrate-specific pathway of regulated RNA degradation, 2-5A-mediated decay (2-5AMD) (Chakrabarti et al, 2011; Cooper et al, 2014b; Donovan et al, 2017; Rath et al, 2015). 2-5AMD is activated in the presence of double-stranded RNA, an immunogen associated with viruses (Li et al, 2016) and pathologic derepression of endogenous repeat elements encoded in host genomes (Chiappinelli et al, 2015; Leonova et al, 2013; Li et al, 2017). 2-5AMD involves the coordinated action of 2-5A synthetases (OASs) and the downstream receptor RNase L
2-5AMD Inhibits Translation Initiation without Disrupting Cap-Binding Complex and 40S Subunit Loading To begin deciphering the mechanism of protein synthesis regulation by 2-5AMD, we examined whether it affects polysomes in wild type (WT) and RNase LÀ/À cells by sucrose gradient sedimentation
Summary
Prangley, et al report that human cells reprioritize translation via cell-wide mRNA destruction in response to doublestranded 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. Highlights d DsRNA rapidly arrests translation using 2-5A/RNase-Lmediated mRNA decay d Defense mRNAs preferentially accumulate due to positive feedback in the IFN response d RNase L-cleaved ribosomes are translationally competent d Human cells have RNase-L-inaccessible poly(A)+ mRNA pools that are not translating.
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