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

Cell Rep. 2019 Mar 19;26(12):3416-3428.e5. 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.

Keywords: PKR; REDD1; fluorescence in situ hybridization; mTOR; nucleus; oxidative stress; retrograde transport; tRNA; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Nucleus / metabolism*
  • Cytoplasm / metabolism*
  • HeLa Cells
  • Humans
  • Oxidative Stress*
  • RNA Transport*
  • RNA, Transfer / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • eIF-2 Kinase / metabolism


  • DDIT4 protein, human
  • Transcription Factors
  • RNA, Transfer
  • MTOR protein, human
  • EIF2AK3 protein, human
  • TOR Serine-Threonine Kinases
  • eIF-2 Kinase