title: Angiogenin-induced tRNA fragments inhibit translation initiation.
abstract: Angiogenin is a stress-activated ribonuclease that cleaves tRNA within anticodon loops to produce tRNA-derived stress-induced fragments (tiRNAs). Transfection of natural or synthetic tiRNAs inhibits protein synthesis and triggers the phospho-eIF2α-independent assembly of stress granules (SGs), essential components of the stress response program. We show that selected tiRNAs inhibit protein synthesis by displacing eIF4G/eIF4A from uncapped > capped RNAs. tiRNAs also displace eIF4F, but not eIF4E:4EBP1, from isolated m(7)G cap. We identify a terminal oligoguanine motif that is required to displace the eIF4F complex, inhibit translation, and induce SG assembly. We show that the tiRNA-associated translational silencer YB-1 contributes to angiogenin-, tiRNA-, and oxidative stress-induced translational repression. Our data reveal some of the mechanisms by which stress-induced tRNA cleavage inhibits protein synthesis and activates a cytoprotective stress response program.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA. pivanov@rics.bwh.harvard.edu
authors.forename: Pavel
authors.initials: P
authors.lastname: Ivanov
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Emara
authors.forename: Judit
authors.initials: J
authors.lastname: Villen
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
mesh_terms: D002460:Cell Line; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism / Q000502:physiology; D006801:Humans; D010442:Peptide Chain Initiation, Translational; D012343:RNA, Transfer / Q000737:chemistry / Q000502:physiology*; D012259:Ribonuclease, Pancreatic / Q000502:physiology*; D013312:Stress, Physiological; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism / Q000502:physiology
chemical_list: C113920:EIF4G1 protein, human; D039603:Eukaryotic Initiation Factor-4G; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D012343:RNA, Transfer; C046366:angiogenin; D012259:Ribonuclease, Pancreatic