eIF2B localisation and its regulation during the integrated stress response is cell type specific

Abstract

Eukaryotic initiation factor 2B (eIF2B) is a master regulator of translation control. eIF2B recycles inactive eIF2-GDP to active eIF2-GTP. Under transient/acute cellular stress, a family of kinases phosphorylate the alpha subunit of eIF2 (eIF2-P[S51]) activating the integrated stress response (ISR). This response pathway inhibits eIF2B activity resulting in overall translation attenuation and reprogramming of gene expression to overcome the stress. The duration of an ISR programme can dictate cell fate wherein chronic activation has pathological outcomes. Vanishing white matter disease (VWMD) is a chronic ISR-related disorder linked to mutations in eIF2B. eIF2B is vital to all cell types, yet VWMD eIF2B mutations primarily affect astrocytes and oligodendrocytes suggesting cell type-specific functions of eIF2B. Regulation of the cytoplasmic localisation of eIF2B (eIF2B bodies) has been implicated in the ISR. Here, we highlight the cell type specific localisation of eIF2B within neuronal and glial cell types. Our analyses revealed that each cell type possesses its own steady-state repertoire of eIF2B bodies with varied subunit composition and activity. We also demonstrate that neural and glial cell types respond similarly to acute induction of the ISR whilst a chronic ISR programme exerts cell type-specific differences. Regulatory composition of eIF2B bodies is suggested to be differentially modulated in a manner that correlates to the action of acute and chronic ISR. We also highlight a cell type specific response of the ISR inhibitor ISRIB on eIF2B localisation and activity.