PT  - JOURNAL ARTICLE
AU  - Sneha Rath
AU  - Eliza Prangley
AU  - Jesse Donovan
AU  - Kaitlin Demarest
AU  - Ned S. Wingreen
AU  - Yigal Meir
AU  - Alexei Korennykh
TI  - Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in dsRNA Response
AID  - 10.1101/484675
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 484675
4099  - http://biorxiv.org/content/early/2018/12/04/484675.short
4100  - http://biorxiv.org/content/early/2018/12/04/484675.full
AB  - RNA degradation by RNase L during 2-5A-mediated decay (2-5AMD) is a conserved mammalian stress response to viral and endogenous double-stranded RNA (dsRNA). 2-5AMD onsets rapidly and facilitates a switch of protein synthesis from homeostasis to production of interferons (IFNs). To understand the mechanism of this protein synthesis reprogramming, we examined 2-5AMD in human cells. 2-5AMD triggers polysome collapse characteristic of a translation initiation defect, but translation initiation complexes and ribosomes purified from the translation-arrested cells remain functional. Using spike-in RNA-seq we found that basal messenger RNAs (mRNAs) rapidly decay, while mRNAs encoding IFNs and IFN-stimulated genes evade 2-5AMD and accumulate. The IFN evasion results from the combined effect of better mRNA stability and positive feedback amplification in the IFN response. Therefore, 2-5AMD and transcription act in concert to revamp the cellular mRNA composition. The resulting preferential accumulation of innate immune mRNAs establishes “prioritized” synthesis of defense proteins.