Angiogenin-Cleaved tRNA Halves Interact with Cytochrome c, Protecting Cells from Apoptosis during Osmotic Stress

• Published in: Molecular and cellular biology Vol. 34; no. 13; pp. 2450 - 2463
• Main Authors: Saikia, Mridusmita, Jobava, Raul, Parisien, Marc, Putnam, Andrea, Krokowski, Dawid, Gao, Xing-Huang, Guan, Bo-Jhih, Yuan, Yiyuan, Jankowsky, Eckhard, Feng, Zhaoyang, Hu, Guo-fu, Pusztai-Carey, Marianne, Gorla, Madhavi, Sepuri, Naresh Babu V., Pan, Tao, Hatzoglou, Maria
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.07.2014; American Society for Microbiology
• Subjects: angiogenin; Animals; apoptosis; 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; cell viability; Cells, Cultured; Cytochromes c - metabolism; Electrophoretic Mobility Shift Assay; Fibroblasts; Mice; mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Neurons - cytology; Neurons - drug effects; Osmotic Pressure; osmotic stress; Ribonuclease, Pancreatic - metabolism; Ribonuclease, Pancreatic - pharmacology; ribonucleoproteins; Ribonucleoproteins - genetics; RNA; RNA Cleavage; RNA, Transfer - metabolism; Sequence Analysis, RNA
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00136-14

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.