Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L

Alisha Chitrakar, Sneha Rath, Jesse Donovan, Kaitlin Demarest, Yize Li, Raghavendra Rao Sridhar, Susan R. Weiss, Sergei V. Kotenko, Ned S. Wingreen, Alexei Korennykh

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Cells of all mammals recognize double-stranded RNA (dsRNA) as a foreign material. In response, they release interferons (IFNs) and activate a ubiquitously expressed pseudokinase/endoribonuclease RNase L. RNase L executes regulated RNA decay and halts global translation. Here, we developed a biosensor for 2′,5′-oligoadeny-late (2-5A), the natural activator of RNase L. Using this biosensor, we found that 2-5A was acutely synthesized by cells in response to dsRNA sensing, which immediately triggered cellular RNA cleavage by RNase L and arrested host protein synthesis. However, translation-arrested cells still transcribed IFN-stimulated genes and secreted IFNs of types I and III (IFN-β and IFN-λ). Our data suggest that IFNs escape from the action of RNase L on translation. We propose that the 2-5A/RNase L pathway serves to rapidly and accurately suppress basal protein synthesis, preserving privileged production of defense proteins of the innate immune system.

Original languageEnglish (US)
Pages (from-to)2103-2111
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number6
DOIs
StatePublished - Feb 5 2019

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • 2-5A
  • Interferon
  • RNA decay
  • RNase L
  • Translation reprogramming

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