RNase L Reprograms Translation by Widespread mRNA Turnover Escaped by Antiviral mRNAs

Mol Cell. 2019 Sep 19;75(6):1203-1217.e5. doi: 10.1016/j.molcel.2019.07.029. Epub 2019 Sep 4.


In response to foreign and endogenous double-stranded RNA (dsRNA), protein kinase R (PKR) and ribonuclease L (RNase L) reprogram translation in mammalian cells. PKR inhibits translation initiation through eIF2α phosphorylation, which triggers stress granule (SG) formation and promotes translation of stress responsive mRNAs. The mechanisms of RNase L-driven translation repression, its contribution to SG assembly, and its regulation of dsRNA stress-induced mRNAs are unknown. We demonstrate that RNase L drives translational shut-off in response to dsRNA by promoting widespread turnover of mRNAs. This alters stress granule assembly and reprograms translation by allowing translation of mRNAs resistant to RNase L degradation, including numerous antiviral mRNAs such as interferon (IFN)-β. Individual cells differentially activate dsRNA responses revealing variation that can affect cellular outcomes. This identifies bulk mRNA degradation and the resistance of antiviral mRNAs as the mechanism by which RNase L reprograms translation in response to dsRNA.

Keywords: PABPC1; PKR; RNase L; dsRNA; eIF2a; innate immune response; interferon; mRNA degradation; mRNA metabolism; stress granule.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • Cellular Reprogramming*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • HEK293 Cells
  • Humans
  • Interferon-beta / biosynthesis*
  • Interferon-beta / genetics
  • Protein Biosynthesis*
  • RNA Stability
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism*


  • RNA, Double-Stranded
  • RNA, Messenger
  • Interferon-beta
  • eIF-2 Kinase
  • Endoribonucleases
  • 2-5A-dependent ribonuclease