eIF2B conformation and assembly state regulate the integrated stress response

Schoof, Michael; Boone, Morgane; Wang, Lan; Lawrence, Rosalie; Frost, Adam; Walter, Peter

doi:10.7554/elife.65703

Cited by 58 publications

(137 citation statements)

References 61 publications

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“…ISRIB counteracts ISR activation by pre-disposing its target eIF2B into an active state that becomes resistant to inhibition by p-eIF2α 52 , 53 . Low p-eIF2α results in ISR that is weakly antagonized by ISRIB 52 , 53 , thus explaining the resistance of WT KRAS tumor cells to ISRIB treatments in mice (Fig. 6a ).…”

Section: Discussionmentioning

confidence: 99%

The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer

et al. 2021

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The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.

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Section: Discussionmentioning

confidence: 99%

The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer

et al. 2021

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“…Interestingly, the supplementation of SFSV NSs to neural cells exhibited neuroprotective effects under the ISR-inducible stressed conditions (Figure 5). The currently identified direct block mechanism of SFSV NSs against eIF2(αP) on eIF2B was more effective than the allosteric antagonism by ISRIB (Schoof et al, 2021; Zyryanova et al, 2021) (Figure 2D). Therefore, these observations raise the possibility that, like ISRIB, SFSV NSs could also show beneficial effects in neuropathological conditions.…”

Section: Results and Discussisonmentioning

confidence: 92%

“…The eIF2B interaction with SFSV NSs is mostly mediated by the α-subunits, and does not induce a large movement in the eIF2B subunits as compared with the apo eIF2B structure (Zyryanova et al, 2021) (Figure S1G). This is in stark contrast to the phosphorylated eIF2α, which binds like a wedge between the α- and δ-subunits of eIF2B and interacts with both subunits extensively, resulting in the structural rearrangement of the eIF2B subunits (Schoof et al, 2021; Zyryanova et al, 2021) (Figures 1B and S1G).…”

Section: Results and Discussisonmentioning

confidence: 97%

“…The property of SFSV NSs, which directly binds to eIF2B and prevents the attenuation of cap-dependent translation, is somewhat similar to that of ISRIB, a small molecule that acts as an allosteric eIF2(αP) antagonist, binding eIF2B to disfavor its interaction with eIF2(αP) (Schoof et al, 2021; Zyryanova et al, 2021). Interestingly, ISRIB has shown promising effects in various animal models of neuropathological conditions, such as traumatic brain injury (Chou et al, 2017), amyotrophic lateral sclerosis (ALS) (Bugallo et al, 2020), Down syndrome (Zhu et al, 2019), and prion disease (Halliday et al, 2015), and even in the normal aging process (Krukowski et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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eIF2B-capturing viral protein NSs suppresses the integrated stress response

Kashiwagi

Shichino

Osaki

et al. 2021

Preprint

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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 nucleotides on unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. 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 exhibits normal nucleotide exchange activity even in the presence of eIF2(αP). A genome-wide ribosome profiling analysis clarified that SFSV NSs in human cultured cells attenuates the ISR. Furthermore, SFSV NSs exhibited neuroprotective effects against the ISR-inducing stress. Since the ISR inhibition is beneficial in various neurological disease models, SFSV NSs is promising as a therapeutic ISR inhibitor.

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“…While it is impossible to isolate the primary event from all downstream regulatory layers, it may be possible to identify a specific target for therapeutic intervention. For example, direct targeting of eIF2B by ISRIB, an ISR inhibitor [65], may be useful since eIF2B-mutant cells exhibit hyper-active ISR [66,67], and since ISR has been implicated in regulation of mTOR signaling in a ROS-dependent manner [68].…”

Section: Discussionmentioning

confidence: 99%

The Energy Status of Astrocytes Is the Achilles’ Heel of eIF2B-Leukodystrophy

Herrero

Daw

Atzmon

et al. 2021

Cells

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Translation initiation factor 2B (eIF2B) is a master regulator of global protein synthesis in all cell types. The mild genetic Eif2b5(R132H) mutation causes a slight reduction in eIF2B enzymatic activity which leads to abnormal composition of mitochondrial electron transfer chain complexes and impaired oxidative phosphorylation. Previous work using primary fibroblasts isolated from Eif2b5(R132H/R132H) mice revealed that owing to increased mitochondrial biogenesis they exhibit normal cellular ATP level. In contrast to fibroblasts, here we show that primary astrocytes isolated from Eif2b5(R132H/R132H) mice are unable to compensate for their metabolic impairment and exhibit chronic state of low ATP level regardless of extensive adaptation efforts. Mutant astrocytes are hypersensitive to oxidative stress and to further energy stress. Moreover, they show migration deficit upon exposure to glucose starvation. The mutation in Eif2b5 prompts reactive oxygen species (ROS)-mediated inferior ability to stimulate the AMP-activated protein kinase (AMPK) axis, due to a requirement to increase the mammalian target of rapamycin complex-1 (mTORC1) signalling in order to enable oxidative glycolysis and generation of specific subclass of ROS-regulating proteins, similar to cancer cells. The data disclose the robust impact of eIF2B on metabolic and redox homeostasis programs in astrocytes and point at their hyper-sensitivity to mutated eIF2B. Thereby, it illuminates the central involvement of astrocytes in Vanishing White Matter Disease (VWMD), a genetic neurodegenerative leukodystrophy caused by homozygous hypomorphic mutations in genes encoding any of the 5 subunits of eIF2B.

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eIF2B conformation and assembly state regulate the integrated stress response

Cited by 58 publications

References 61 publications

The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer

The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer

eIF2B-capturing viral protein NSs suppresses the integrated stress response

The Energy Status of Astrocytes Is the Achilles’ Heel of eIF2B-Leukodystrophy

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