Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation

Abstract

Ribosome stalling during translation has recently been shown to cause neurodegeneration, yet the signaling pathways triggered by stalled elongation complexes are unknown. To investigate these pathways we analyzed the brain of C57BL/6J-Gtpbp2nmf205-/- mice in which neuronal elongation complexes are stalled at AGA codons due to deficiencies in a tRNAArgUCU tRNA and GTPBP2, a mammalian ribosome rescue factor. Increased levels of phosphorylation of eIF2α (Ser51) were detected prior to neurodegeneration in these mice and transcriptome analysis demonstrated activation of ATF4, a key transcription factor in the integrated stress response (ISR) pathway. Genetic experiments showed that this pathway was activated by the eIF2α kinase, GCN2, in an apparent deacylated tRNA-independent fashion. Further we found that the ISR attenuates neurodegeneration in C57BL/6J-Gtpbp2nmf205-/- mice, underscoring the importance of cellular and stress context on the outcome of activation of this pathway. These results demonstrate the critical interplay between translation elongation and initiation in regulating neuron survival during cellular stress.DOI: http://dx.doi.org/10.7554/eLife.14295.001

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Thus, while the subtle translation elongation defect caused by the reduction of n-Tr20 expression in B6J mice is normally compensated for by GTPBP2, in its absence, prolonged ribosome stalls persist and cause neurodegeneration. Deletion of the n-Tr20 gene, resulting in a complete absence of mature n-Tr20 tRNA, severely exacerbated the phenotype of the Gtpbp2 -/- mice, resulting in neonatal lethality and suggesting that the residual amount of mature n-Tr20 in B6J mice is sufficient to allow postnatal survival of the double mutants (Ishimura et al, 2016). Although Gtpbp2 is ubiquitously expressed, the phenotype in double mutants is confined to the nervous system, indicating that the brain-specific expression pattern of n-Tr20 may underlie the specificity of disease.…”

“…Clearly, failure to recycle stalled ribosomes in mammalian neurons leads to neurodegeneration; however, the underlying molecular mechanism and signaling pathways that lead to cell death remain unknown (Ishimura et al, 2016). In investigating this question, Ishimura et al discovered an exciting link between the dysfunction of translational elongation and regulation of initiation.…”

Factors That Shape Eukaryotic tRNAomes: Processing, Modification and Anticodon–Codon Use

“…In this case a second homolog may increase global tRNA modifications in a tissue- or time-specific manner, e.g., to aid development, or perhaps associated with a tissue-specific tRNA. Although some tRNAs are expressed in a tissue-specific manner, these have been associated with shifts in the total pool [162], whereas in some cases individual tRNAs have been documented to be restricted to the central nervous system and are known to be important determinants of development [14,163]. We are unaware of a specific link between a tissue-specific modification and a tissue-specific tRNA.…”

“…47 tRNA anticodon families in mammals are multicopy, mutation to an individual tRNA gene might not be expected to be pathologic. However, this perspective was overturned upon report of a mutation in a central nervous system-specific tRNA Arg UCU gene that is associated with widespread neurodegeneration in mouse [14,163]. This reflects a highly specific association between a defective tRNA and neuropathology but adds to what appears to be a more general association between defects in tRNA biogenesis–metabolism modifications and neurodevelopmental disorders [36].…”

“…The single gene Mendelian model of disease clearly applies to the disorders caused by mutations in tRNA-associated enzymes as well as mutation to the central nervous system (CNS)-specific tRNA Arg UCU gene itself that is associated with neurodegeneration [14,163]. However, there is another view of how disturbances of tRNA pool homeostasis may influence common disorders for which there are genetic influences, namely, as a disease modifier.…”