Oxidative Stress Triggers Selective tRNA Retrograde Transport in Human Cells during the Integrated Stress Response

• Published in: Cell reports (Cambridge) 2019-03, Vol.26 (12), p.3416-3428.e5
• Main Authors: Schwenzer, Hagen, Jühling, Frank, Chu, Alexander, Pallett, Laura J., Baumert, Thomas F., Maini, Mala, Fassati, Ariberto
• Format: Article
• Language: English
• Subjects: Cell Nucleus - metabolism; Cytoplasm - metabolism; eIF-2 Kinase - metabolism; fluorescence in situ hybridization; HeLa Cells; Human health and pathology; Humans; Life Sciences; mTOR; nucleus; Oxidative Stress; PKR; REDD1; retrograde transport; RNA Transport; RNA, Transfer - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Transcription Factors - metabolism; tRNA; unfolded protein response
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.02.077

In eukaryotes, tRNAs are transcribed in the nucleus and exported to the cytosol, where they deliver amino acids to ribosomes for protein translation. This nuclear-cytoplasmic movement was believed to be unidirectional. However, active shuttling of tRNAs, named tRNA retrograde transport, between the cytosol and nucleus has been discovered. This pathway is conserved in eukaryotes, suggesting a fundamental function; however, little is known about its role in human cells. Here we report that, in human cells, oxidative stress triggers tRNA retrograde transport, which is rapid, reversible, and selective for certain tRNA species, mostly with shorter 3′ ends. Retrograde transport of tRNASeC, which promotes translation of selenoproteins required to maintain homeostatic redox levels in cells, is highly efficient. tRNA retrograde transport is regulated by the integrated stress response pathway via the PERK-REDD1-mTOR axis. Thus, we propose that tRNA retrograde transport is part of the cellular response to oxidative stress. [Display omitted] •Oxidative stress triggers nuclear import of cytoplasmic tRNAs•Import is selective for certain tRNAs•Import requires activation of the unfolded protein response and inhibition of mTOR via REDD1•tRNA nuclear import is a component of the integrated stress response Schwenzer et. al discovered that oxidative stress induces nuclear import of cytoplasmic tRNAs. The authors found that this pathway is activated during the integrated stress response. tRNA nuclear import was selective to certain tRNA species and may contribute to the changes in protein translation known to protect cells from stress.