Angiogenin cleaves tRNA and promotes stress-induced translational repression

J Cell Biol. 2009 Apr 6;185(1):35-42. doi: 10.1083/jcb.200811106. Epub 2009 Mar 30.


Stress-induced phosphorylation of eIF2alpha inhibits global protein synthesis to conserve energy for repair of stress-induced damage. Stress-induced translational arrest is observed in cells expressing a nonphosphorylatable eIF2alpha mutant (S51A), which indicates the existence of an alternative pathway of translational control. In this paper, we show that arsenite, heat shock, or ultraviolet irradiation promotes transfer RNA (tRNA) cleavage and accumulation of tRNA-derived, stress-induced small RNAs (tiRNAs). We show that angiogenin, a secreted ribonuclease, is required for stress-induced production of tiRNAs. Knockdown of angiogenin, but not related ribonucleases, inhibits arsenite-induced tiRNA production and translational arrest. In contrast, knockdown of the angiogenin inhibitor RNH1 enhances tiRNA production and promotes arsenite-induced translational arrest. Moreover, recombinant angiogenin, but not RNase 4 or RNase A, induces tiRNA production and inhibits protein synthesis in the absence of exogenous stress. Finally, transfection of angiogenin-induced tiRNAs promotes phospho-eIF2alpha-independent translational arrest. Our results introduce angiogenin and tiRNAs as components of a phospho-eIF2alpha-independent stress response program.

Publication types

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

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / physiology
  • Cell Line
  • Gene Expression Regulation* / radiation effects
  • Heat-Shock Response
  • Humans
  • Oxidative Stress
  • Protein Biosynthesis* / radiation effects
  • RNA, Transfer / biosynthesis
  • RNA, Transfer / metabolism*
  • RNA, Transfer / physiology
  • Recombinant Fusion Proteins / metabolism
  • Ribonuclease, Pancreatic / genetics
  • Ribonuclease, Pancreatic / physiology*
  • Stress, Physiological*
  • Ultraviolet Rays


  • Carrier Proteins
  • RNH1 protein, human
  • Recombinant Fusion Proteins
  • RNA, Transfer
  • angiogenin
  • Ribonuclease, Pancreatic