Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation
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 s...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/14295 |
| _version_ | 1811228054211526656 |
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| author | Ryuta Ishimura Gabor Nagy Ivan Dotu Jeffrey H Chuang Susan L Ackerman |
| author_facet | Ryuta Ishimura Gabor Nagy Ivan Dotu Jeffrey H Chuang Susan L Ackerman |
| author_sort | Ryuta Ishimura |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:52:03Z |
| format | Article |
| id | doaj.art-4e33e8f16d1c4cf9ad15a0bfcbf9450b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:52:03Z |
| publishDate | 2016-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4e33e8f16d1c4cf9ad15a0bfcbf9450b2022-12-22T03:37:48ZengeLife Sciences Publications LtdeLife2050-084X2016-04-01510.7554/eLife.14295Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiationRyuta Ishimura0Gabor Nagy1Ivan Dotu2Jeffrey H Chuang3Susan L Ackerman4https://orcid.org/0000-0002-6740-593XHoward Hughes Medical Institute, The Jackson Laboratory for Mammalian Genetics, Bar Harbor, United StatesHoward Hughes Medical Institute, The Jackson Laboratory for Mammalian Genetics, Bar Harbor, United StatesResearch Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, SpainThe Jackson Laboratory for Genomic Medicine, Farmington, United States; Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, United StatesHoward Hughes Medical Institute, The Jackson Laboratory for Mammalian Genetics, Bar Harbor, United States; Department of Cell and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, United States; Section of Neurobiology, University of California, La Jolla, United StatesRibosome 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.https://elifesciences.org/articles/14295translation elongationneurodegenerationtranslation initiation |
| spellingShingle | Ryuta Ishimura Gabor Nagy Ivan Dotu Jeffrey H Chuang Susan L Ackerman Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation eLife translation elongation neurodegeneration translation initiation |
| title | Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation |
| title_full | Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation |
| title_fullStr | Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation |
| title_full_unstemmed | Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation |
| title_short | Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation |
| title_sort | activation of gcn2 kinase by ribosome stalling links translation elongation with translation initiation |
| topic | translation elongation neurodegeneration translation initiation |
| url | https://elifesciences.org/articles/14295 |
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