title: Angiogenin-cleaved tRNA halves interact with cytochrome c, protecting cells from apoptosis during osmotic stress.
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.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Mridusmita
authors.initials: M
authors.lastname: Saikia
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Jobava
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Parisien
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Putnam
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Dawid
authors.initials: D
authors.lastname: Krokowski
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Xing-Huang
authors.initials: XH
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Bo-Jhih
authors.initials: BJ
authors.lastname: Guan
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Jankowsky
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Guo-fu
authors.initials: GF
authors.lastname: Hu
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Pusztai-Carey
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Andhra Pradesh, India.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Gorla
authors.affiliation: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Andhra Pradesh, India.
authors.forename: Naresh Babu V
authors.initials: NB
authors.lastname: Sepuri
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA mxh8@case.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053478:Apoptosomes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009997:Osmotic Pressure; D059367:RNA Cleavage; D012343:RNA, Transfer / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000378:metabolism* / Q000494:pharmacology; D012261:Ribonucleoproteins / Q000235:genetics; D017423:Sequence Analysis, RNA
chemical_list: C506593:Apaf1 protein, mouse; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D012261:Ribonucleoproteins; D045304:Cytochromes c; D012343:RNA, Transfer; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D053148:Caspase 3; D053453:Caspase 9
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