Cellular eIF2B subunit localisation: implications for the integrated stress response and its control by small molecule drugs

HODGSON, Rachel E., VARANDA, Beatriz A., ASHE, Mark P., ALLEN, K.E. and CAMPBELL, Susan (2019). Cellular eIF2B subunit localisation: implications for the integrated stress response and its control by small molecule drugs. Molecular biology of the cell, 30 (8), 933-1049.

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Official URL: https://www.molbiolcell.org/doi/10.1091/mbc.E18-08...
Link to published version:: https://doi.org/10.1091/mbc.E18-08-0538

Abstract

eIF2 is a G protein critical for translation. It is tightly regulated in the integrated stress response (ISR) via phosphorylation of eIF2α and the subsequent control of eIF2B, a multisubunit guanine nucleotide exchange factor (GEF). Through studying the localisation of eIF2B subunits we identified cytoplasmic eIF2B bodies in mammalian cells. We highlight a relationship between body size and the eIF2B subunits localising to them; larger bodies contain all subunits and smaller bodies contain predominantly catalytic subunits. eIF2 localises to eIF2B bodies and shuttles within these bodies in a manner which correlates with eIF2B activity. Upon stress eIF2α-P localises predominately to larger bodies and results in a decreased shuttling of eIF2. Interestingly drugs which inhibit the ISR can rescue eIF2 shuttling in a manner correlating to levels of eIF2α-P. In contrast, smaller bodies show increased eIF2 shuttling in response to stress, which is accompanied by the localisation of eIF2Bδ to these bodies, suggesting the formation of a novel trimeric complex of eIF2B. This response is mimicked by ISR inhibiting drugs, providing insight into their potential mechanism of action. This study provides evidence that the composition and function of mammalian eIF2B bodies is regulated by the ISR and drugs which control it.

Item Type: Article
Additional Information: ** From Crossref via Jisc Publications Router **Journal IDs: pissn 1059-1524; eissn 1939-4586 **History: published 06-02-2019
Uncontrolled Keywords: Cell Biology, Molecular Biology
Identification Number: https://doi.org/10.1091/mbc.E18-08-0538
SWORD Depositor: Louise Beirne
Depositing User: Louise Beirne
Date Deposited: 15 Feb 2019 09:43
Last Modified: 04 Sep 2019 08:30
URI: http://shura.shu.ac.uk/id/eprint/24036

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