Angiogenin-Induced tRNA Fragments Inhibit Translation Initiation

SummaryAngiogenin 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 m7G 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.

► Selected 5′-tiRNAs target eIF4G/A to inhibit translation in reticulocyte lysates ► A terminal oligoguanine motif is required for tiRNA-induced translational repression ► 5′-tiRNAs cooperate with YB-1 to promote stress granule assembly ► YB-1 is required for optimal 5′-tiRNA- and arsenite-induced translational repression