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.
Original language | American English |
---|---|
Pages (from-to) | 1218-1228.e6 |
Journal | Molecular cell |
Volume | 75 |
Issue number | 6 |
DOIs | |
State | Published - Sep 19 2019 |
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Keywords
- RNase L
- dsRNA
- innate immunity
- interferon
- mRNA decay
- reprogramming
- translation