EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response.

Stephanie L Moon,Roy Parker

doi:10.1261/rna.066563.118

Abstract

Mutations in eIF2B genes cause vanishing white matter disease (VWMD), a fatal leukodystrophy that can manifest following physical trauma or illness, conditions that activate the integrated stress response (ISR). EIF2B is the guanine exchange factor for eIF2, facilitating ternary complex formation and translation initiation. During the ISR, eIF2α is phosphorylated and inhibits eIF2B, causing global translation suppression and stress-induced gene translation, allowing stress adaptation and recovery. We demonstrate that VWMD patient cells hypersuppress translation during the ISR caused by acute ER stress, delaying stress-induced gene expression and interrupting a negative feedback loop that allows translational recovery by GADD34-mediated dephosphorylation of phospho-eIF2α. Thus, cells from VWMD patients undergo a prolonged state of translational hyperrepression and fail to recover from stress. We demonstrate that small molecules targeting eIF2B or the eIF2α kinase PERK rescue translation defects in patient cells. Therefore, defects in the ISR could contribute to white matter loss in VWMD.

Highlights

Vanishing white matter disease (VWMD), a fatal leukodystrophy in children and adults, is caused by mutations in any of the five EIF2B genes (Leegwater et al 2001)
Because the eIF2B complex is important for both normal translation activity and regulation of translation activity during stress, EIF2B mutations causative of vanishing white matter disease (VWMD) could cause a global reduction in translation activity, and/or perturb the integrated stress response
We addressed these possibilities as follows using three immortalized lymphoblast cell lines derived from patients with VWMD caused by mutations in the EIF2B2 subunit, as compared to three age, sex- and ethnicity-matched control cell lines

Summary

Introduction

Vanishing white matter disease (VWMD), a fatal leukodystrophy in children and adults, is caused by mutations in any of the five EIF2B genes (Leegwater et al 2001). EIF2B is an important translation initiation factor that is targeted early in the ISR to mediate the translational repression arm of this pathway This suggested the hypothesis that disease-causing mutations in EIF2B genes alter the cellular response to stress by perturbing the regulation of translation during the ISR. The eIF2B complex is a dimer of heteropentamers (Gordiyenko et al 2014; Kashiwagi et al 2016) that exchanges GDP for GTP on eIF2 to allow ternary complex formation and translation initiation. During stresses such as viral infections and ER stress, the eIF2 complex is targeted by stress-activated protein kinases that phosphorylate eIF2α

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Conclusion