EIF2B-capturing viral protein NSs suppresses the integrated stress response
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ABSTRACT:
PROVIDER: PRJNA731488 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14605917.fastq.gz | Fastqsanger.gz | |||
| SRR14605918.fastq.gz | Fastqsanger.gz | |||
| SRR14605919.fastq.gz | Fastqsanger.gz | |||
| SRR14605920.fastq.gz | Fastqsanger.gz | |||
| SRR14605921.fastq.gz | Fastqsanger.gz |
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Project description:Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis revealed that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibited neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs is promising as a therapeutic ISR inhibitor.
2021-11-11 | GSE174764 | GEO
Project description:Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis reveals that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibits neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs may be a promising therapeutic ISR inhibitor.
| S-EPMC8651795 | biostudies-literature
Project description:Purpose: The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We performed RNA-seq analysis of cerebellum collected from mice harboring a homozygous point mutation in eIF2B5 (HO R191H), a mutation that causes a severe form of VWM in humans and compared gene expression to wildtype age-matched littermates to identify transcriptomic differences at early, mid and late time points during disease progression. We also performed RNA-seq on cerebellum collected from animals treated with the eIF2B activator 2BAct for 1 month to determine to what extent small molecule treatment could normalize the VWM transcriptome. Methods: Samples were collected at 2, 5, and 7 months of age. In addition, HO R191H and WT mice treated with and without with the eIF2B activator 2BAct for 1 month were profiled. RNA-seq libraries were prepared using purified RNA isolated from frozen tissue using the RNeasy Mini kit. RNA quality and concentration were assayed using a Fragment Analyzer instrument. RNA-seq libraries were prepared using the TruSeq Stranded Total RNA kit paired with the Ribo-Zero rRNA removal kit. Libraries were sequenced on an Illumina HiSeq 4000 instrument. For the experiment comparing different ages, N = 3 males/genotype/time point. For the 4-week 2BAct treatment experiment, N = 3 females/condition. Conclusions: HO R191H mutant brains show an elevated gene expression signature of the Integrated Stress Reponse in mice as early as 2 months, preceding the appearance of overt pathology in these animals. The expression of the ISR-related genes does not significantly increases at 5 months and 7 months of age. One month of treatment with 2BAct completely prevented the expression of ISR-related in genes in 2 month old animals.
2019-03-11 | GSE128092 | GEO
Project description:eIF2B is a master regulator of translation initiation and mediator of the integrated stress response (ISR). Partial-loss-of function mutations are associated with eIF2B-leukodystrophy termed Vanishing White Matter Disease (VWMD), a recessive neurodegenerative disorder. Astrocytes, the brain homeostasis keepers, are central to VWMD owing to their hyper-sensitivity to eIF2B activity, as manifested by their phenotypic deficits due to the mutation. Here we used astrocytes isolated from the brains of WT and eIF2B5R132H/R132H mice to assess their transcriptome and translatome responses upon cytokine-mediated activation, an mTOR-driven process critical for brain homeostasis. We found that: (i) a mild eIF2B mutation has the power to disrupt translation regulation programs involving ~30% of the expressed genes; (ii) a common compensatory strategy to overcome the translation regulation failure is manipulation of mRNA abundance; and (iii) dysregulation of functionally related genes can be used to reliably predict deficits of corresponding cellular functions. Specifically, the study illuminates the molecular anomalies responsible for the impaired ribogenesis and mitochondrial respiration of eIF2B-mutant astrocytes. Moreover, it reliably predicts, for the first time, impaired cholesterol biosynthesis in eIF2B-mutant astrocytes. This work demonstrates the strength of combined transcriptome/translatome approach to decipher links between mild expression anomalies and downstream cellular defects associated with VWMD.
2025-03-19 | GSE252362 | GEO
Project description:Transcriptomic profiling of a eIF2B mutant mouse with a chronic Integrated Stress Response
| PRJNA526445 | ENA
Project description:Protein synthesis is an essential cellular process highly deregulated in multiple tumour types, where control of several translation factors is hijacked to benefit oncogenic growth. Here we show that colorectal cancer (CRC) is characterized specifically by elevated levels of phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2alpha). In contrast to its canonical association with reduced translation rates, we reveal that CRC with high p-eIF2alpha has increased protein synthesis rates. Thus, we hypothesize that eIF2B, the sensor of p-eIF2 alpha, plays a central role in cells’ inability to relay this inhibitory signal. Using a combination of in cellulo biochemistry, phenotypic assays, and analysis of translation upon modulation of eIF2B subunits alpha and delta, the two eIF2B subunits responsible for sensing p-eIF2 alpha, we demonstrate that CRC cells require an intact eIF2B complex to sense p-eIF2 alpha. Crucially, we show that the alpha subunit of eIF2B is necessary to translate the oncogenic programs driven by APC loss, highlighting its central role in oncogenic transformation. To conclude, we demonstrate that whilst normal cells do not depend on eIF2B alpha, CRC cells require this eIF2B subunit for correct sensing of p-eIF2 alpha and regulation of their proteostasis, thus validating eIF2B alpha as a target for therapeutic intervention in CRC.
2025-01-09 | GSE249128 | GEO
Project description:Genome-wide mRNA expression in brains of wild-type and eIF2B-R132H/R132H mutant mice (Geva et al., BRAIN 133 (8), 2010) profiled at postnatal (P) days 1, 18 and 21 to reflect the early proliferative stage prior to white matter establishment (P1) and the peak of oligodendrocye differentiation and myelin synthesis (P18 and P21). 3 biological replicates (whole brain without the cerebellum) from each wild-type and eIF2B-R132H/R132H mutant mice at 3 postnatal (P) days 1, 18 and 21 were used for RNA extraction and hybridization on Affymetrix microarrays.
2011-11-14 | E-GEOD-32201 | biostudies-arrayexpress
Project description:Decreased nucleotide exchange activity of the eukaryotic translation initiation factor eIF2B coupled with increased phosphorylation of eIF2alpha (eIF2alpha-p) is a hallmark of the “canonical” integrated stress response (c-ISR). In mammals, however, it is unclear whether decreased eIF2B activity in absence of alterations in eIF2alpha-p which occurs in human disease including leukodystrophies, is synonymous to c-ISR. Herein, we describe a previously unknown mechanism of adaptation to decreased eIF2B activity, distinct from c-ISR, which we term “split” ISR (s-ISR). We demonstrate that s-ISR comprises translation reprogramming of only a subset of c-ISR mRNA targets which is accompanied by distinct transcriptomes. In contrast to c-ISR, s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (e.g., PCK2), resulting in metabolic adaptations to maintain cellular bioenergetics under conditions of low eIF2B activity. Overall, these data demonstrate hitherto-unappreciated plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of increased eIF2-p, activates an eIF4E/ATF4/PCK2 axis to maintain energy homeostasis.
2025-01-22 | GSE268132 | GEO
Project description:Decreased nucleotide exchange activity of the eukaryotic translation initiation factor eIF2B coupled with increased phosphorylation of eIF2alpha (eIF2alpha-p) is a hallmark of the “canonical” integrated stress response (c-ISR). In mammals, however, it is unclear whether decreased eIF2B activity in absence of alterations in eIF2alpha-p which occurs in human disease including leukodystrophies, is synonymous to c-ISR. Herein, we describe a previously unknown mechanism of adaptation to decreased eIF2B activity, distinct from c-ISR, which we term “split” ISR (s-ISR). We demonstrate that s-ISR comprises translation reprogramming of only a subset of c-ISR mRNA targets which is accompanied by distinct transcriptomes. In contrast to c-ISR, s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (e.g., PCK2), resulting in metabolic adaptations to maintain cellular bioenergetics under conditions of low eIF2B activity. Overall, these data demonstrate hitherto-unappreciated plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of increased eIF2-p, activates an eIF4E/ATF4/PCK2 axis to maintain energy homeostasis.
2025-01-22 | GSE268127 | GEO
Project description:Decreased nucleotide exchange activity of the eukaryotic translation initiation factor eIF2B coupled with increased phosphorylation of eIF2alpha (eIF2alpha-p) is a hallmark of the “canonical” integrated stress response (c-ISR). In mammals, however, it is unclear whether decreased eIF2B activity in absence of alterations in eIF2alpha-p which occurs in human disease including leukodystrophies, is synonymous to c-ISR. Herein, we describe a previously unknown mechanism of adaptation to decreased eIF2B activity, distinct from c-ISR, which we term “split” ISR (s-ISR). We demonstrate that s-ISR comprises translation reprogramming of only a subset of c-ISR mRNA targets which is accompanied by distinct transcriptomes. In contrast to c-ISR, s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (e.g., PCK2), resulting in metabolic adaptations to maintain cellular bioenergetics under conditions of low eIF2B activity. Overall, these data demonstrate hitherto-unappreciated plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of increased eIF2-p, activates an eIF4E/ATF4/PCK2 axis to maintain energy homeostasis.
2025-01-22 | GSE268130 | GEO