Viral Evasion of the Integrated Stress Response Through Antagonistic eIF2-P Mimicry

Schoof, Michael; Wang, Lan; Cogan, J. Zachery; Lawrence, Rosalie; Boone, Morgane; Wuerth, Jennifer Deborah; Frost, Adam; Walter, Peter

doi:10.1101/2021.06.07.447473

Cited by 2 publications

(1 citation statement)

References 62 publications

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“…eIF2B activity is dynamically modulated by the integrated stress response (ISR), an evolutionarily conserved signaling pathway that is activated in response to diverse cellular stresses, such as viral infection, amino acid deprivation, protein misfolding, and oxidative stress (Pakos-Zebrucka, Koryga et al 2016 , Costa-Mattioli andWalter 2020 ). ISR activation centers on the phosphorylation eIF2B binding partner, eIF2, which led to structural changes that alter its interaction with eIF2B, turning it from a substrate into a competitive inhibitor of the guanine nucleotide exchange factor (GEF) activity of eIF2B (Adomavicius, Guaita et al 2019, Gordiyenko, Llacer et al 2019, Kenner, Anand et al 2019, Schoof, Boone et al 2021 ). As a result, the availability of eIF2-GTP and the subsequent TC become limited, leading to attenuation of global translation.…”

Section: Introductionmentioning

confidence: 99%

DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response

Yulyaningsih,

Suh,

Fanok

et al. 2023

Preprint

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The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models – the optic nerve crush injury and an eIF2B loss of function (LOF) mutant – demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.

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Section: Introductionmentioning

confidence: 99%

DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response

Yulyaningsih,

Suh,

Fanok

et al. 2023

Preprint

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A point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by allosteric modulation

Wang

Boone

Lawrence

et al. 2021

Preprint

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In eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic translation initiation factor eIF2 (eIF2-P), which ultimately leads to reduced levels of ternary complex required for initiation of mRNA translation. Translational control is primarily exerted through a conformational switch in eIF2’s nucleotide exchange factor, eIF2B, which shifts from its active A-State conformation to its inhibited I-State conformation upon eIF2-P binding, resulting in reduced nucleotide exchange on eIF2. Here, we show functionally and structurally how a single histidine to aspartate point mutation in eIF2B’s β subunit (H160D) mimics the effects of eIF2-P binding by promoting an I-State like conformation, resulting in eIF2-P independent activation of the ISR. These findings corroborate our previously proposed (Schoof et al. 2021) A/I-State model of allosteric ISR regulation.

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Viral Evasion of the Integrated Stress Response Through Antagonistic eIF2-P Mimicry

Cited by 2 publications

References 62 publications

DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response

DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response

A point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by allosteric modulation

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