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

Molecular Biology of the Cell
Rachel E HodgsonSusan G Campbell


Eukaryotic initiation factor 2 (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 eukaryotic initiation factor 2B (eIF2B), a multisubunit guanine nucleotide exchange factor. Through studying the localization of eIF2B subunits, we identified cytoplasmic eIF2B bodies in mammalian cells. We highlight a relationship between body size and the eIF2B subunits localizing to them; larger bodies contain all subunits and smaller bodies contain predominantly catalytic subunits. eIF2 localizes to eIF2B bodies and shuttles within these bodies in a manner that correlates with eIF2B activity. On stress, eIF2α-P localizes predominately to larger bodies and results in a decreased shuttling of eIF2. Interestingly, drugs that 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 localization 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. ...Continue Reading


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Methods Mentioned

nucleotide exchange
fluorescence recovery after photobleaching
confocal microscopy
dot blot
protein assay

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