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

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• dc.contributor.author Ishimura, Ryuta
• dc.contributor.author Nagy, Gabor
• dc.contributor.author Dotu, Ivan
• dc.contributor.author Chuang, Jeffrey H.
• dc.contributor.author Ackerman, Susan L.
• dc.date.accessioned 2024-01-23T07:22:17Z
• dc.date.available 2024-01-23T07:22:17Z
• dc.date.issued 2016
• dc.description.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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Ishimura R, Nagy G, Dotu I, Chuang JH, Ackerman SL. Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation. eLife. 2016 Apr 16;5:e14295. DOI: 10.7554/eLife.14295
• dc.identifier.doi http://dx.doi.org/10.7554/eLife.14295
• dc.identifier.issn 2050-084X
• dc.identifier.uri http://hdl.handle.net/10230/58802
• dc.language.iso eng
• dc.publisher eLife
• dc.relation.ispartof eLife. 2016 Apr 16;5:e14295
• dc.relation.isreferencedby https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE79930
• dc.rights © 2016, Ishimura et al.This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Ribosomes
• dc.subject.other Mamífers
• dc.subject.other Experimentació animal
• dc.title Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion