Cited by 221RNA and protein synthesis mechanismsEndoplasmic Reticulum Stress and DiseaseAutophagy in Disease and Therapy

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

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Ishimura, Ryuta, Nagy, Gabor, Dotu, Ivan, Chuang, Jeffrey H, Ackerman, Susan L·2016·eLife

DOI 10.7554/elife.14295PMC PMC4917338

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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.

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Figure 1. Transcriptional profiling of B6J-Gtpbp2nmf205-/- mutant mice. (A) To segregate genes associated with ribosome stalling from genes nonspecifically induced during neurodegeneration, microarray analysis was performed on the cerebellum (Cb) and hippocampus (Hp) from B6J and B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-) mice at 3-weeks (3W) and 5-weeks (5W) of age. (B) Enriched pathways among genes that were up or downregulated in the B6J-Gtpbp2nmf205-/- brain were obtained by Kegg pathway analysis. Note that upregulated gene pathways exhibited more robust p-values. (C) Ingenuity Pathway Analysis (IPA) upstream regulator analysis of B6J-Gtpbp2nmf205-/- upregulated genes demonstrates ATF4 and EIF2AK3 activation in the 3- and 5-week hippocampus and cerebellum. Inflammatory-related upstream regulators are also strongly activated of in the 5-week-old mutant cerebellum. (D) Volcano plots of –log10q-values and relative fold changes of all genes. Genes previously shown to be expressed in microglia (red), astrocytes (green), or in both microglia and astrocytes (blue) are indicated, with all other genes shown in gray. Genes with very high levels of induction are shown in boxes to fit on the scale. The horizontal dashed lines indicate a false discovery rate of 0.1. Note the strong induction of genes activated in both microglia and astrocytes in the 5-week-old B6-Gtpbp2nmf205-/- cerebellum. (E) Immunofluorescence using antibodies to Iba1 (microglia) and GFAP (astrocytes) was performed on sections of B6J and B6J-Gtpbp2nmf205-/- cerebellum at indicated ages. Microglia and astrocytes were activated in the mutant cerebellum with highest levels of activation at 5 weeks of age. Sections were counterstained with Hoechst 33342 to visualize nuclei as shown in merged. Scale bar, 50 μm. DOI: http://dx.doi.org/10.7554/eLife.14295.003CC BY · PubMed Central

Figure 1—figure supplement 1. Progressive neurodegeneration in B6J-Gtpbp2nmf205-/-mice. Hematoxylin and eosin-stained sagittal sections of the B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-) and B6J cerebellum at the ages shown. Higher-magnification images of cerebellar lobule IX are shown. Scale bars, 1 mm (upper row), and 50 μm (lower row). DOI: http://dx.doi.org/10.7554/eLife.14295.007CC BY · PubMed Central

Figure 1—figure supplement 2. Neurodegeneration is reduced in hippocampus of B6J-Gtpbp2nmf205-/- mice. Hematoxylin and eosin-stained sagittal sections of hippocampus (HP) in B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-) at 3- and 5-weeks of age and B6J (wild type) at 5-weeks of age. Higher-magnification images of the dentate gyrus (DG) are shown. Scale bars, 500 μm (top row), and 50 μm (bottom row). DOI: http://dx.doi.org/10.7554/eLife.14295.008CC BY · PubMed Central

Figure 1—figure supplement 3. Microarray analysis of the B6J and B6J-Gtpbp2nmf205-/- cerebellum. Volcano plots of microarray results of cerebellar and hippocampal transcripts from 3- and 5-week-old B6J and B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-) mice. Thresholds of a relative fold change of 1.5 fold (vertical lines) and a q-value of 0.05 (horizontal lines) were adopted for this study. DOI: http://dx.doi.org/10.7554/eLife.14295.009CC BY · PubMed Central

Figure 1—figure supplement 4. The inflammatory response in the B6J-Gtpbp2nmf205-/- hippocampus. Antibodies against Iba1 and GFAP assessed activation of microglia and astrocyte, respectively in CA1 (A) and dentate gyrus (B) of B6J and B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-). Sections were counterstained with Hoechst 33,342 to visualize nuclei as shown in merged images. For comparative purposes, images were taken with an identical exposure time as those in Figure 1E. Scale bar, 50 μm. DOI: http://dx.doi.org/10.7554/eLife.14295.010CC BY · PubMed Central

Figure 2. ATF4 downstream genes are robustly activated in B6J-Gtpbp2nmf205-/- mutant brain. (A) Volcano plots of ATF4 downstream genes demonstrating activation of the ATF4 pathway in the B6J- Gtpbp2nmf205-/- (B6J-nmf205-/-) brain. Fold change and q values of all genes are shown and ATF4 target genes, obtained from previous ChIP-Seq studies as described in the text, are red. Genes with very high levels of induction are shown in boxes to fit on the scale. Note that although induction of ATF4 downstream genes is observed in all groups, upregulation of these genes occurs earlier and is most robust in the cerebellum. (B) Venn diagram of differentially expressed genes between B6J and B6J-Gtpbp2nmf205-/- 3-and 5-week cerebellum and 5-week hippocampus. Note that a large number of genes (56 genes) are consistently upregulated between cerebellum and hippocampus and that most of these genes are known ATF4 target genes. (C) The distribution of ATF4 target genes in the upregulated gene set from the B6J-Gtpbp2nmf205-/- 3-week hippocampus. (D) The relative fold change (RFC) of the top ten upregulated genes in the 3-week-old B6J- Gtpbp2nmf205-/- cerebellum for each time point and brain region. RFCs depicted with solid bars were significant changes (p<0.05) and those depicted by hatched bars were not. DOI: http://dx.doi.org/10.7554/eLife.14295.011CC BY · PubMed Central

Figure 3. GCN2 mediates eIF2α phosphorylation and ATF4 activation in the B6J-Gtpbp2nmf205-/- brain. (A) Western blot analysis of cerebellar extracts from 3-week-old mice incubated with the antibodies shown (left panel). The relative abundance of phospho-eIF2α (Ser51) to total eIF2α was averaged for three biological replicates (right panel). Values are shown relative to B6J. (B) The effect of Gcn2 deletion on the 146 genes upregulated or the 191 genes downregulated by 1.5 fold (padj < 0.01) in the cerebellum of B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-) relative to that of B6J (left and right diagram, respectively). ATF4 target status of the 83 genes that are upregulated in the B6J-Gtpbp2nmf205-/- cerebellum relative to B6J and that also have a significant decrease in expression in the B6J-Gtpbp2nmf205-/-; Gcn2-/- cerebellum relative to B6J- Gtpbp2nmf205-/- (middle diagram). (C) Fold change of upregulated ATF4 downstream genes from B6J-Gcn2-/-, B6J-Gtpbp2nmf205-/-, and B6J-Gtpbp2nmf205-/-; Gcn2-/-mice relative to B6J expression. The 10 most upregulated genes in cerebellum of B6J-Gtpbp2nmf205-/-mice relative to that B6J are shown. Note that the increased expression of these GCN2-ATF4 downstream genes in the B6J-Gtpbp2nmf205-/- cerebellum was completely suppressed by deletion of Gcn2. Error bars = SEM. *p<0.05, **p<0.01, and ***p<0.001 (one-way ANOVA, A, C). DOI: http://dx.doi.org/10.7554/eLife.14295.014CC BY · PubMed Central

Figure 3—figure supplement 1. Absence of changes in Xbp1 splicing in the B6J-Gtpbp2nmf205-/- brain. RT-PCR was performed to assess splicing of the Xbp1 mRNA in 3-week-old cerebellum (A), and 4-week-old cerebellum and hippocampus (B) in B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-) mice. NIH3T3 cells were untreated or treated with thapsigargin (Thaps.) as a negative and positive control, respectively, for Xbp1 splicing. DOI: http://dx.doi.org/10.7554/eLife.14295.018CC BY · PubMed Central

Figure 3—figure supplement 2. Quantitative RT-PCR showing the induction of ATF4 downstream genes is under the control of GCN2. RT-qPCR was performed on the cerebellar transcripts from B6J, B6J.Gcn2-/-, B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-), and B6J- Gtpbp2nmf205-/- (B6J-nmf205-/-); Gcn2-/- 3-week-old mice for the top 5 ATF4 downstream genes that had the highest relative fold change in the 3-week-old B6J-Gtpbp2nmf205-/- cerebellum in the microarray study. Expression levels were normalized by Gapdh expression, and relative fold change was calculated relative to the expression of the B6J cerebellum. Three mice from each genotype were analyzed and error bars indicate SEMs. ***p<0.001. DOI: http://dx.doi.org/10.7554/eLife.14295.019CC BY · PubMed Central

Figure 3—figure supplement 3. RNA-Seq analysis. Volcano plots of pairwise genotype comparisons of transcripts from RNA-SEQ analysis performed on the cerebellum of 3-week-old B6J, B6J. Gcn2-/-, B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-), and B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-); Gcn2-/- mice. Thresholds of a relative fold change of 1.5 fold (vertical lines) and a p-value of 0.05 (horizontal lines) were adopted for this study. DOI: http://dx.doi.org/10.7554/eLife.14295.020CC BY · PubMed Central

Figure 3—figure supplement 4. Deletion of Gcn2 decreases expression of ATF4 target genes in the B6J cerebellum. RT-qPCR analysis was performed on ATF4 target genes in the cerebellum from 2-month-old B6J, B6J.B6Nn-Tr20 and B6J. Gcn2-/- mice. Expression levels were normalized to Gapdh expression (n=4 mice per genotype). Error bars = SEM. *p<0.05 (Student's t tests). DOI: http://dx.doi.org/10.7554/eLife.14295.021CC BY · PubMed Central

Figure 4. GCN2 activation in the B6J-Gtpbp2nmf205-/- brain is independent of uncharged tRNAArgUCU and unprocessed n-Tr20 tRNA. (A) Northern blot analysis of cerebellar RNA from 3-week-old B6J and B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-) mice using pooled probes to n-Tr21/22/23/25 tRNAs to assess the expression levels of the tRNAArgUCU isodecoder family. 5S was used as internal control. (B) Charged (pH 5) and uncharged (pH 9) tRNAArgUCU levels in the 3-week-old B6J and B6J-Gtpbp2nmf205-/- cerebellum. Note that the levels of uncharged tRNAArgUCU are negligible in both the B6J-Gtpbp2nmf205-/- and B6J cerebellum. A short (right) and a longer (left) exposure are shown. (C–E) RT-qPCR analysis of expression of ATF4 target genes. (C) Overexpression of the mutant n-Tr20 tRNA does not change expression of ATF4 targets in the 3-week-old cerebellum although increased levels of unprocessed n-Tr20 are present. (n=3 mice per genotype) (D) Overexpression of the mutant n-Tr20 tRNA does not change expression of ATF4 targets even in the Gtpbp2nmf205-/- mutant cerebellum at 3 weeks of age. (n=3) (E) ATF4 targets are significantly upregulated in the P0 brain of B6J-n-Tr20-/-; Gtpbp2nmf205-/- mice, although no unprocessed or uncharged forms of n-Tr20 are present. (n=4 mice per genotype) Error bars = SEM. *p<0.05, **p<0.01, and ***p<0.001 (Student's unpaired two-tailed t tests, C, E; one-way ANOVA, D). DOI: http://dx.doi.org/10.7554/eLife.14295.022CC BY · PubMed Central

Figure 4—figure supplement 1. Generation of mice overexpressing mutant n-Tr20. (A) Schematic showing 1.2-kb long genomic region around n-Tr20 containing the B6J SNP (indicated with an asterisk) that was used to produce transgenic mice. (B) Northern blot analysis using whole brain RNA comparing the expression pattern of n-Tr20 in B6N and B6J and the transgenic founder lines. Based on the amount of the 115-nt unprocessed form, line Tg681 has the highest expression of the mutant transgene and hence was chosen for the further experiments described in this paper. DOI: http://dx.doi.org/10.7554/eLife.14295.023CC BY · PubMed Central

Figure 4—figure supplement 2. Generation of mice with the deleted n-Tr20 allele. (A) LoxP sites were introduced flanking the n-Tr20 locus were introduced by homologous recombination as shown in the schematic. n-Tr20 was deleted in the germline by crossing B6J mice carrying the floxed allele to B6J-EIIa-Cre mice. (B) PCR analysis of genomic DNA using the indicated primers confirmed Cre-excision of n-Tr20. (C) Northern blot analysis showing complete loss of n-Tr20 expression in B6J-n-Tr20-/- brain. For comparison, levels of n-Tr20 are shown in the B6J and B6N brain. DOI: http://dx.doi.org/10.7554/eLife.14295.024CC BY · PubMed Central

Figure 5. Loss of GCN2 accelerates B6J-Gtpbp2nmf205-/- cerebellar degeneration. (A) Hematoxylin and eosin- stained sagittal sections of B6J.Gcn2-/-, B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-), B6J-Gtpbp2nmf205-/-; Gcn2-/- and B6J cerebella. Higher-magnification images of cerebellar lobule IX and lobule VI are shown on lower panels. Scale bars, 1 mm (top row), and 50 μm (bottom two rows). (B) Numbers of granule cells (n=3 mice/genotype). Means ± SEM are shown. *p<0.05, **p<0.01, and ***p< 0.001 (one-way ANOVA). DOI: http://dx.doi.org/10.7554/eLife.14295.025CC BY · PubMed Central

Figure 6. GCN2 protects against loss of B6J-Gtpbp2nmf205-/- CA1 hippocampal neurons. (A) Hematoxylin and eosin stained sagittal sections of 6-week-old B6J.Gcn2-/-, B6J-Gtpbp2nmf205-/- (B6J-nmf205-/-), B6J- Gtpbp2nmf205-/-; Gcn2-/-, and B6J hippocampi. Higher magnification images of hippocampal CA1 are also shown. Scale bars, 250 μm (left panels), 100 μm (middle panels), and 20 μm (right panels). DOI: http://dx.doi.org/10.7554/eLife.14295.026CC BY · PubMed Central

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Authors: Ishimura, R., Nagy, G., Dotu, I., Chuang, J. H., & Ackerman, S. L.
Affiliations: Howard Hughes Medical Institute (US)
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
The Jackson Laboratory for Genomic Medicine (US)
Corresponding author: Ackerman, Susan L
ORCID: Chuang, Jeffrey H
Ackerman, Susan L
Venue: eLife
Publisher: eLife Sciences Publications, Ltd
Published: 2016-04-16
Volume: 5
ISSN: 2050-084X (ISSN-L)
DOI: 10.7554/elife.14295
PMC: PMC4917338
OpenAlex: W2341404981
Cited by: 221
References: 92
Citations by year: 2026: 27 · 2025: 38 · 2024: 31 · 2023: 23 · 2022: 19 · 2021: 25 · 2020: 24 · 2019: 14 · 2018: 14 · 2017: 6
FWCI: 5.89
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
creativecommons.org/licenses/by/4.0/ (am)
creativecommons.org/licenses/by/4.0/ (tdm)
Locations: eLife (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
eScholarship (California Digital Library) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by)
The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
Funders: National Institute of Neurological Disorders and Stroke (NS094637)
Howard Hughes Medical Institute
National Human Genome Research Institute (HG007554)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords: GCN2, ribosome stalling, translation elongation, translation initiation, integrated stress response, eIF2α phosphorylation, ATF4, neurodegeneration, neuronal stress response, neuronal survival
MeSH terms: Animals, Mice, Inbred C57BL, Neurons, Peptide Chain Elongation, Translational, Peptide Chain Initiation, Translational, Phosphorylation, Protein Processing, Post-Translational, Ribosomes, RNA, Transfer, Arg, Eukaryotic Initiation Factor-2, Protein Serine-Threonine Kinases, GTP-Binding Proteins, Gene Expression Profiling, Activating Transcription Factor 4

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

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