Stress-Induced Translation Inhibition through Rapid Displacement of Scanning Initiation Factors

Bresson, Stefan; Shchepachev, Vadim; Spanos, Christos; Turowski, Tomasz W.; Rappsilber, Juri; Tollervey, David

doi:10.1016/j.molcel.2020.09.021

Cited by 76 publications

(96 citation statements)

References 83 publications

(132 reference statements)

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“…In contrast to these increases, following glucose starvation, the number of cells displaying eIF2B bodies slightly decreased for all strains W303-1A, eIF2Bγ–GFP (46%), S288c, eIF2Bγ–GFP (37%), and BY4741 eIF2Bγ–GFP (6%); however, compared with synthetic complete media (SCD), these differences were not found to be statistically significant. These results are consistent with data showing that eIF2B is not directly involved in translational control following glucose starvation ( 37 , 38 , 39 ). Overall, these results suggest that under normal growth, the level of eIF2B localization to bodies depends on the S. cerevisiae strain, but that the trends in terms of responses to nutritional stress are similar and are dependent on stresses that target eIF2B activity.…”

Section: Resultssupporting

confidence: 93%

Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease

Norris

Hodgson

Dornelles

et al. 2021

Journal of Biological Chemistry

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Eukaryotic initiation factor 2B (eIF2B) serves as a vital control point within protein synthesis and regulates translation initiation in response to cellular stress. Mutations within eIF2B result in the fatal disease, leukoencephalopathy with vanishing white matter (VWM). Previous biochemical studies on VWM mutations have illustrated that changes in the activity of eIF2B poorly correlate with disease severity. This suggests that there may be additional characteristics of eIF2B contributing to VWM pathogenesis. Here, we investigated whether the localization of eIF2B to eIF2B bodies was integral for function and whether this localization could provide insight into the pathogenesis of VWM. We demonstrate that the regulatory subunit, eIF2Bα, is required for the assembly of eIF2B bodies in yeast and that loss of eIF2B bodies correlates with an inability of cells to regulate eIF2B activity. Mutational analysis of eIF2Bα showed that missense mutations that disrupt the regulation of eIF2B similarly disrupt the assembly of eIF2B bodies. In contrast, when eIF2Bα mutations that impact the catalytic activity of eIF2B were analyzed, eIF2B bodies were absent and instead eIF2B localized to small foci, termed microfoci. Fluorescence recovery after photobleaching analysis highlighted that within these microfoci, eIF2 shuttles more slowly indicating that formation of eIF2B bodies correlates with full eIF2B activity. When eIF2Bα VWM mutations were analyzed, a diverse impact on localization was observed, which did not seem to correlate with eIF2B activity. These findings provide key insights into how the eIF2B body assembles and suggest that the body is a fundamental part of the translational regulation via eIF2α phosphorylation.

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Section: Resultssupporting

confidence: 93%

Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease

Norris

Hodgson

Dornelles

et al. 2021

Journal of Biological Chemistry

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“…This result suggests that Mrn1 may play a distinctive role in response to glucose withdrawal. Mrn1 may also respond to heat stress, as it was strongly depleted from mRNAs after heat shock [12].…”

Section: Introductionmentioning

confidence: 99%

Dynamic post-transcriptional regulation by Mrn1 links cell wall homeostasis to mitochondrial structure and function

Reynaud

Brothers

et al. 2021

PLoS Genet

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The RNA-binding protein Mrn1 in Saccharomyces cerevisiae targets over 300 messenger RNAs, including many involved in cell wall biogenesis. The impact of Mrn1 on these target transcripts is not known, however, nor is the cellular role for this regulation. We have shown that Mrn1 represses target mRNAs through the action of its disordered, asparagine-rich amino-terminus. Its endogenous targets include the paralogous SUN domain proteins Nca3 and Uth1, which affect mitochondrial and cell wall structure and function. While loss of MRN1 has no effect on fermentative growth, we found that mrn1Δ yeast adapt more quickly to respiratory conditions. These cells also have enlarged mitochondria in fermentative conditions, mediated in part by dysregulation of NCA3, and this may explain their faster switch to respiration. Our analyses indicated that Mrn1 acts as a hub for integrating cell wall integrity and mitochondrial biosynthesis in a carbon-source responsive manner.

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“…How the FTO preferentially binds to Mmp24 mRNA under the neuropathic pain condition is unclear. This could be due to that the binding of FTO and Mmp24 mRNA in the spinal cord is regulated by nerve injury-sensitive signaling pathways ( Bresson et al, 2020 ), such as the upregulation of mediators in promoting the interaction of FTO and Mmp24 mRNA or downregulation of competitors in competing for the binding between FTO and Mmp24 mRNA ( Song et al, 2019 ; Ontiveros et al, 2020 ). Although demethylase FTO, as an “eraser”, removed the m 6 A in Mmp24 mRNA after SNL, the specific “reader” decoding the m 6 A modification in the Mmp24 mRNA remains unknown.…”

Section: Discussionmentioning

confidence: 99%

MMP24 Contributes to Neuropathic Pain in an FTO-Dependent Manner in the Spinal Cord Neurons

Huang

Zhang

et al. 2021

Front. Pharmacol.

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Nerve injury-induced gene expression change in the spinal cord is critical for neuropathic pain genesis. RNA N6-methyladenosine (m6A) modification represents an additional layer of gene regulation. We showed that spinal nerve ligation (SNL) upregulated the expression of matrix metallopeptidase 24 (MMP24) protein, but not Mmp24 mRNA, in the spinal cord neurons. Blocking the SNL-induced upregulation of spinal MMP24 attenuated local neuron sensitization, neuropathic pain development and maintenance. Conversely, mimicking MMP24 increase promoted the spinal ERK activation and produced evoked nociceptive hypersensitivity. Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA Immunoprecipitation (RIP) assay indicated the decreased m6A enrichment in the Mmp24 mRNA under neuropathic pain condition. Moreover, fat-mass and obesity-associated protein (FTO) was colocalized with MMP24 in spinal neurons and shown increased binding to the Mmp24 mRNA in the spinal cord after SNL. Overexpression or suppression of FTO correlates with promotion or inhibition of MMP24 expression in cultured spinal cord neurons. In conclusion, SNL promoted the m6A eraser FTO binding to the Mmp24 mRNA, which subsequently facilitated the translation of MMP24 in the spinal cord, and ultimately contributed to neuropathic pain genesis.

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Stress-Induced Translation Inhibition through Rapid Displacement of Scanning Initiation Factors

Cited by 76 publications

References 83 publications

Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease

Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease

Dynamic post-transcriptional regulation by Mrn1 links cell wall homeostasis to mitochondrial structure and function

MMP24 Contributes to Neuropathic Pain in an FTO-Dependent Manner in the Spinal Cord Neurons

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