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

Sneha Rath, Eliza Prangley, Jesse Donovan, Kaitlin Demarest, Ned S. Wingreen, Yigal Meir, Alexei Korennykh

Research output: Contribution to journalArticle

5 Scopus citations

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 languageEnglish (US)
Pages (from-to)1218-1228.e6
JournalMolecular Cell
Volume75
Issue number6
DOIs
StatePublished - Sep 19 2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

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

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