Angiogenin-cleaved tRNA halves interact with cytochrome c, protecting cells from apoptosis during osmotic stress

Mol Cell Biol. 2014 Jul;34(13):2450-63. doi: 10.1128/MCB.00136-14. Epub 2014 Apr 21.


Adaptation to changes in extracellular tonicity is essential for cell survival. However, severe or chronic hyperosmotic stress induces apoptosis, which involves cytochrome c (Cyt c) release from mitochondria and subsequent apoptosome formation. Here, we show that angiogenin-induced accumulation of tRNA halves (or tiRNAs) is accompanied by increased survival in hyperosmotically stressed mouse embryonic fibroblasts. Treatment of cells with angiogenin inhibits stress-induced formation of the apoptosome and increases the interaction of small RNAs with released Cyt c in a ribonucleoprotein (Cyt c-RNP) complex. Next-generation sequencing of RNA isolated from the Cyt c-RNP complex reveals that 20 tiRNAs are highly enriched in the Cyt c-RNP complex. Preferred components of this complex are 5' and 3' tiRNAs of specific isodecoders within a family of isoacceptors. We also demonstrate that Cyt c binds tiRNAs in vitro, and the pool of Cyt c-interacting RNAs binds tighter than individual tiRNAs. Finally, we show that angiogenin treatment of primary cortical neurons exposed to hyperosmotic stress also decreases apoptosis. Our findings reveal a connection between angiogenin-generated tiRNAs and cell survival in response to hyperosmotic stress and suggest a novel cellular complex involving Cyt c and tiRNAs that inhibits apoptosome formation and activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Apoptosomes / antagonists & inhibitors
  • Apoptosomes / biosynthesis*
  • Apoptotic Protease-Activating Factor 1 / genetics
  • Base Sequence
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Survival
  • Cells, Cultured
  • Cytochromes c / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Fibroblasts
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Osmotic Pressure
  • RNA Cleavage*
  • RNA, Transfer / metabolism*
  • Ribonuclease, Pancreatic / metabolism*
  • Ribonuclease, Pancreatic / pharmacology
  • Ribonucleoproteins / genetics
  • Sequence Analysis, RNA


  • Apaf1 protein, mouse
  • Apoptosomes
  • Apoptotic Protease-Activating Factor 1
  • Ribonucleoproteins
  • Cytochromes c
  • RNA, Transfer
  • angiogenin
  • Ribonuclease, Pancreatic
  • Caspase 3
  • Caspase 9

Associated data

  • GEO/GSE57435