The Role of eIF2B Localisation in Cell-specific Stress Responses

Abstract

Eukaryotic initiation factor 2B (eIF2B) is a guanine nucleotide exchange factor (GEF) and 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 at serine 51 (eIF2α-P) activating the integrated stress response (ISR). This response pathway inhibits eIF2B activity resulting in overall translation attenuation and reprogramming of gene expression to overcome cellular stress. The duration of an ISR programme can dictate cell fate wherein chronic activation is adaptive to prologued stress but has pathological outcomes. Leukoencephalopathy with 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, also termed eIF2B bodies,has been implicated in the ISR. The work in this dissertation reveals that eIF2B localisation is cell-type specific in neuronal and glial cells. Each cell type possesses its own steady-state repertoire of eIF2B bodies with varying eIF2B subunit composition and GEF activity. This thesis also reports that neuronal and glial cells respond similarly to acute induction of the ISR whilst chronic ISR exerts cell-type specific differences. Herein, eIF2Bδ composition of eIF2B bodies is differentially modulated in a manner that correlates to the action of acute and chronic ISR. This dissertation also reports cell-type specific responses of the chemical inhibitor of the ISR (ISRIB) on eIF2Bδ composition and GEF activity of eIF2B bodies, providing evidence of a cell-specific action of ISRIB.