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

Abstract

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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Nov 23, 2019·Wiley Interdisciplinary Reviews. RNA·Mariavittoria PizzingaAnne E Willis
Apr 16, 2020·Molecular Biology of the Cell·Guendalina MariniGaia Pigino
Mar 24, 2020·Biochemistry·Assen Marintchev, Takuhiro Ito
May 7, 2021·The Journal of Neuropsychiatry and Clinical Neurosciences·Catalina CosteiRoberta La Piana

Methods Mentioned

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

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