Abstract
SummaryIn 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.
Highlights
As adaptor molecules for the translational machinery, tRNAs transport their cognate amino acids to cytoplasmic ribosomal complexes, translating the genetic information of mRNA into nascent polypeptide chains (Soll and RajBhandary, 1995)
The fraction contained tRNAs mostly with defective 30 CCA ends, and we demonstrated that such defective tRNAs were efficiently imported into the nucleus in an energydependent manner (Zaitseva et al, 2006), suggesting that HIV-1 co-opts the physiological import of certain tRNA species for its own nuclear import. tRNA nuclear import has since been reported in rat hepatoma cells (Shaheen et al, 2007), Chinese hamster ovary cells (Barhoom et al, 2011), and human 293T cells (Miyagawa et al, 2012; Watanabe et al, 2013)
TRNALys was mainly detected in the cytoplasm, whereas U5 snRNA was detected in the nucleus only
Summary
As adaptor molecules for the translational machinery, tRNAs transport their cognate amino acids to cytoplasmic ribosomal complexes, translating the genetic information of mRNA into nascent polypeptide chains (Soll and RajBhandary, 1995). The dogma of unidirectional movement held that tRNAs are produced inside the nucleus and exported into the cytoplasm to function in protein translation (Soll and RajBhandary, 1995) This tenet of unidirectional transport was initially challenged by the observation that, in yeast, tRNAs are spliced on the surface of mitochondria, but spliced tRNAs were detected inside the nucleus (Yoshihisa et al, 2003). TRNA nuclear import has since been reported in rat hepatoma cells (Shaheen et al, 2007), Chinese hamster ovary cells (Barhoom et al, 2011), and human 293T cells (Miyagawa et al, 2012; Watanabe et al, 2013) This pathway is called ‘‘tRNA retrograde transport’’ (Hopper, 2013)
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