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

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

Author information

1
Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
2
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
3
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
4
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, Ohio, USA.
5
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
6
Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Andhra Pradesh, India.
7
Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA mxh8@case.edu.

Abstract

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.

PMID:
24752898
PMCID:
PMC4054315
DOI:
10.1128/MCB.00136-14
[Indexed for MEDLINE]
Free PMC Article

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