Title | Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Rath, S, Prangley, E, Donovan, J, Demarest, K, Wingreen, NS, Meir, Y, Korennykh, A |
Journal | Mol Cell |
Volume | 75 |
Issue | 6 |
Pagination | 1218-1228.e6 |
Date Published | 2019 Sep 19 |
ISSN | 1097-4164 |
Keywords | A549 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> |
DOI | 10.1016/j.molcel.2019.07.027 |
Alternate Journal | Mol Cell |
PubMed ID | 31494033 |
PubMed Central ID | PMC6754276 |
Grant List | F99 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 |