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A stress-induced tyrosine-tRNA depletion response mediates codon-based translational repression and growth suppression.

ABSTRACT: Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine-tRNA_GUA fragments in human cells-causing significant depletion of the precursor tRNA. Tyrosine-tRNA_GUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNA_GUA or its translationally regulated targets USP3 and SCD repressed proliferation-revealing a dedicated tRNA-regulated growth-suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease-dependent manner and inhibit hnRNPA1-mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans-acting small RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon-based regulatory response inherent to the genetic code.

SUBMITTER: Huh D

PROVIDER: S-EPMC7809793 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A stress-induced tyrosine-tRNA depletion response mediates codon-based translational repression and growth suppression.

Huh Doowon D Passarelli Maria C MC Gao Jenny J Dusmatova Shahnoza N SN Goin Clara C Fish Lisa L Pinzaru Alexandra M AM Molina Henrik H Ren Zhiji Z McMillan Elizabeth A EA Asgharian Hosseinali H Goodarzi Hani H Tavazoie Sohail F SF

The EMBO journal 20201221 2

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine-tRNA<sub>GUA</sub> fragments in human cells-causing significant depletion of the precursor tRNA. Tyrosine-tRNA<sub>GUA</sub> depletion impaired translation of growth and metabo ...[more]

PMID: 33346941

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Project description:The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.

Dataset Information

A stress-induced tyrosine-tRNA depletion response mediates codon-based translational repression and growth suppression.

Publications

A stress-induced tyrosine-tRNA depletion response mediates codon-based translational repression and growth suppression.

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