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Title: Stress modulators encoded by African swine fever virus
Author: Barber , Claire Annette
ISNI:       0000 0004 5918 8095
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2015
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The ER responds to the accumulation of unfolded or misfolded proteins by activating the unfolded protein response (UPR) in an attempt to restore homeostasis. One way homeostasis is achieved is through the activation of PERK which leads to the phosphorylation of elF2a and subsequent inhibition of global protein synthesis. Although most mRNAs are not translated during ER stress, the transcription factor ATF4 is still synthesised. A downstream target of ATF4 is the pro-apoptotic transcription factor, CHOP, which is responsible for most ER stress related apoptosis. The consequence of this during infection is inhibition of viral replic'ation. African swine fever virus (ASFV) encodes DP71L, a small protein that shares sequence similarity to both cellular GADD34 and the neurovirulence factor ICP34.5 of Herpesvirus. It has previously been shown that, like ICP34.5 and GADD34, DP71L recruits PPl to dephosphorylate elF2a, and so restores global protein synthesis and inhibits CHOP activation. In this thesis, residues required for the wild type function of DP71L were identified through mutagenesis studies. It has previously been demonstrated that deleting DP71L from ASFV does not result in an increase in elF2a phosphorylation or induction of CHOP during infection. In order to identify other virally encoded genes with a similar function, a library of plasmids, each expressing a single HA-tagged ASFV gene, was evaluated for their ability to inhibit CHOP activation post treatment with the ER stress inducer, tunicamycin . Three candidate genes were identified and these are A179L, K145R and D129L. A179L is a Bci2 homologue and has been shown to inhibit apoptosis and autophagy. However, little is known about K145R and D129L. A yeast two hybrid screen was performed in order to identify interacting partners, and provide some insight into how these novel CHOP inhibitors may function. In addition, their role during ASFV infection was investigated by construction of ASFV gene deletion mutants.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available