Why the study?
It remains unknown how widespread RNA decay and consequent changes in the translatome following RNase L activation promote the elimination of viruses.
RNase L activation triggers translation of alternative ORFs from mRNA decay fragments, potentially producing short peptides important for antiviral activity.
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RNase L activation promotes noncanonical ORF translation during antiviral responses; extends mechanistic understanding but leaves open therapeutic targeting.
Ribonuclease L (RNase L) is activated as part of the innate immune response and plays an important role in the clearance of viral infections. When activated, it endonucleolytically cleaves both viral and host RNAs, leading to a global reduction in protein synthesis. However, it remains unknown how widespread RNA decay, and consequent changes in the translatome, promote the elimination of viruses. To study how this altered transcriptome is translated, we assayed the global distribution of ribosomes in RNase L activated human cells with ribosome profiling. We found that RNase L activation leads to a substantial increase in the fraction of translating ribosomes in ORFs internal to coding sequences (iORFs) and ORFs within 5' and 3' UTRs (uORFs and dORFs). Translation of these alternative ORFs was dependent on RNase L's cleavage activity, suggesting that mRNA decay fragments are translated to produce short peptides that may be important for antiviral activity.
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Karasik et al. (2021) studied this question.
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