The ubiquitin pathway in host-parasite interactions during infection by Trichinella spiralis

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Title: The ubiquitin pathway in host-parasite interactions during infection by Trichinella spiralis
Authors: White, Rhiannon Rose
Item Type: Thesis or dissertation
Abstract: These studies present the identification of the first parasite secreted ubiquitin pathway enzyme, and report a system for the characterisation of the role of Trichinella spiralis secreted proteins in the context of mammalian muscle cell re-programming. T. spiralis invade terminally differentiated myofibres, secreting proteins (SP) into the host cell and inducing dedifferentiation and cell cycle re-entry. Since myogenic differentiation and the cell cycle are heavily influenced by the ubiquitin pathway, this study used T. spiralis as a model to investigate the extent to which parasites specifically manipulate the ubiquitin pathway during infection. Ubiquitin is ligated to protein substrates by E1, E2 and E3 enzymes, and removed by deubiquitinating enzymes (DUBs). This ubiquitin 'tag' regulates the fate and function of the substrate protein. A DUB expressed by T. spiralis, TsUCH37, was characterised as a conserved proteasome interaction partner, however no evidence was found of the presence of this, or any other T. spiralis DUB in the muscle larvae SP. Upon further investigation an E2 enzyme, TsUBE2L3, was identified. The ubiquitin conjugation activity of T. spiralis SP was confirmed, and was only possible in the presence of human E1 and E3 enzyme partners. The effect of TsUBE2L3 on mammalian muscle cells was investigated by expressing the T. spiralis protein in a mouse muscle cell line. Although no significant effect on the cell cycle or differentiation state of the muscle cells was observed, TsUBE2L3 expression led to a significant reduction of the tumour suppressor protein, p53 that was confirmed to occur at the protein level. T. spiralis strikes a delicate balance between host cell modulation and host protection. This thesis builds on the proposal that the host-targeted muscle cell modulators of T. spiralis may inspire the development of parasite-derived therapeutics for the treatment of disease.
Content Version: Open Access
Issue Date: Jan-2014
Date Awarded: Mar-2014
URI: http://hdl.handle.net/10044/1/30661
DOI: https://doi.org/10.25560/30661
Supervisor: Artavanis-Tsakonas, Katerina
Gounaris, Niki
Sponsor/Funder: Medical Research Council (Great Britain)
Department: Life Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Life Sciences PhD theses



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