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Mol Cell. 2019 Sep 19;75(6):1218-1228.e6. doi: 10.1016/j.molcel.2019.07.027. Epub 2019 Sep 4.

Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response.

Author information

1
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
2
Department of Physics, Ben Gurion University, Beer-Sheva 84105, Israel.
3
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: akorenny@princeton.edu.

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.

KEYWORDS:

RNase L; dsRNA; innate immunity; interferon; mRNA decay; reprogramming; translation

PMID:
31494033
PMCID:
PMC6754276
[Available on 2020-09-19]
DOI:
10.1016/j.molcel.2019.07.027

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