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

TitleConcerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response.
Publication TypeJournal Article
Year of Publication2019
AuthorsRath, S, Prangley, E, Donovan, J, Demarest, K, Wingreen, NS, Meir, Y, Korennykh, A
JournalMol Cell
Volume75
Issue6
Pagination1218-1228.e6
Date Published2019 09 19
ISSN1097-4164
KeywordsA549 Cells, Endoribonucleases, Humans, Immunity, Innate, Protein Biosynthesis, RNA Stability, RNA, Double-Stranded, RNA, Messenger, Transcription, Genetic
Abstract

<p>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.</p>

DOI10.1016/j.molcel.2019.07.027
Alternate JournalMol. Cell
PubMed ID31494033
PubMed Central IDPMC6754276
Grant ListF99 CA212468 / CA / NCI NIH HHS / United States
K00 CA212468 / CA / NCI NIH HHS / United States
R01 GM110161 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States