eIF2B regulation and localisation in yeast as a response to alcohols

Abstract

A key step in eukaryotic translation initiation is the recycling of the eukaryotic initiation factor, eIF2 from a GDP to GTP-bound translationally competent form. This nucleotide exchange reaction is mediated by eukaryotic translation initiation factor 2B (eIF2B). A range of starvation or stress conditions can inhibit translation by inducing the phosphorylation of the alpha subunit of eIF2 converting eIF2 from a substrate to an inhibitor of eIF2B. In addition, eIF2B localises to a large cytoplasmic body termed the '2B body', which appears important for translation activity and regulation. In yeasts, eIF2B is targeted to inhibit translation by various quorum-sensing alcohols. Toxicity of alcohols, such as butanol, is a major concern for industrial scale butanol production; therefore, the identification and characterisation of butanol resistant strains may well prove important in the search for commercial alternatives to fossil fuel products. In this study, specific eIF2B mutants are shown to have an altered response to alcohols and starvation and exhibit distinctive alterations in the dynamics and morphology of the 2B body. Purification, then proteomic and functional analysis of eIF2B suggests that alcohols act directly to inhibit guanine nucleotide exchange activity and that eIF2B may be associated with fatty acid and pyrimidine metabolic enzymes. Overall these data highlight the possibility that the eIF2B and the 2B body may serve as a hub connecting metabolic signalling with the control of translation initiation.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Ashe (Supervisor) & Graham Pavitt (Supervisor)