Why the study?
The mechanisms of RNase L-driven translation repression, its contribution to stress granule assembly, and its regulation of dsRNA stress-induced mRNAs were unknown.
RNase L reprograms translation during the dsRNA response by degrading bulk mRNA while allowing antiviral mRNAs to escape, revealing a novel mechanism of host shutoff.
Preclinical RNase L mechanism warrants caution extrapolating to human antiviral responses; leaves open its role in cardiac viral infections.
SUMMARY In response to foreign and endogenous double-stranded RNA (dsRNA), protein kinase R (PKR) and ribonuclease L (RNase L) reprogram translation in mammalian cells. PKR inhibits translation initiation through eIF2α phosphorylation, which triggers stress granule (SG) formation and promotes translation of stress responsive mRNAs. The mechanisms of RNase L-driven translation repression, its contribution to SG assembly, and its regulation of dsRNA stress-induced mRNAs are unknown. We demonstrate that RNase L drives translational shut-off in response to dsRNA by promoting widespread turnover of mRNAs. This alters stress granule assembly and reprograms translation by only allowing for the translation of mRNAs resistant to RNase L degradation, including numerous antiviral mRNAs such as IFN-β . Individual cells differentially activate dsRNA responses revealing variation that can affect cellular outcomes. This identifies bulk mRNA degradation and the resistance of antiviral mRNAs as the mechanism by which RNaseL reprograms translation in response to dsRNA.
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Burke et al. (2018) studied this question.
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