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Title: eIF2B bodies and their role in the control of protein synthesis
Author: Norris, Karl Francis
ISNI:       0000 0004 7655 7841
Awarding Body: Sheffield Hallam University
Current Institution: Sheffield Hallam University
Date of Award: 2018
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The eukaryotic initiation factor 2B (eIF2B) serves as a vital control point within translation initiation. eIF2B initiates translation by exchanging GDP for GTP on eIF2. However, this mechanism may be attenuated in response to cellular stress by the phosphorylation of eIF2, which paradoxically enhances the translation of stress-specific mRNA to instigate a stress response. Autosomal recessive mutations within eIF2B result in the disease leukoencephalopathy with vanishing white matter (VWM). Current models of VWM disease suggest that abnormal eIF2B results in the cell being in a constant state of stress. However, previous biochemical studies have illustrated that VWM mutations not only decrease the catalytic activity of eIF2B, but can increase activity or not affect it at all. Furthermore, changes in the activity eIF2B do not correlate with disease severity. These observations suggest that there may be additional characteristics of eIF2B contributing to VWM pathogenesis which remain to be elucidated. In this study, we investigated whether the localisation of eIF2B to eIF2B bodies was integral for function. Using the yeast S. cerevisiae, we show that the regulatory subunit eIF2Bα is required for localisation. Interestingly, catalytic mutations in eIF2Bα localised eIF2B to several smaller foci, termed microbodies. In vivo FRAP analysis highlighted that eIF2 shuttles through microbodies slower than eIF2B bodies, indicating that localisation to eIF2B bodies may be required for full eIF2B activity. Surprisingly, phenotypes from eIF2Bα VWM missense mutations were highly variable in localisation, possibly recapitulating variable phenotypes observed in humans. The putative membrane proteins Mst27p, Erp4p and Sac1p have been shown to associate with eIF2B. We therefore investigated whether they were required for the formation of eIF2B bodies. Deletion of membrane proteins did not significantly alter eIF2B localisation. Surprisingly however, deletion of the PI(4)P Sac1p reduced rates of translation initiation independently of eIF2B, highlighting a link between membrane integrity and translational control.
Supervisor: Campbell, Susan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available