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Subversion of both the actin and microtubule cytoskeletons during vaccinia virus infection

Scaplehorn, Niki James; (2004) Subversion of both the actin and microtubule cytoskeletons during vaccinia virus infection. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Viral and bacterial pathogens offer unparalleled opportunities to dissect signal transduction networks, since infection is often driven by exploitation of cellular controls. In following thesis, two different features of vaccinia virus infection are used to identify mechanisms by which mammalian cells regulate actin nucleation and centrosome stability. Upon leaving the cell, vaccinia virus generates a dynamic, actin-rich structure called an actin tail, which propels it into neighbouring cells. To achieve this, vaccinia stimulates localised tyrosine phosphorylation to assemble a multiprotein actin-nucleation complex. In the first part of the thesis, Grb2 was identified as a component of this complex. Grb2 is recruited both through an interaction between its SH2 domain and A36R Y132, and between its SH3 domains and the N-WASP poly-proline rich region. Grb2 is not necessary for actin tail formation, and is not sufficient to efficiently recruit N-WASP in the absence of Nck. Grb2 does however increase the frequency of actin tails, and so acts as a "secondary" adaptor. Further studies showed that phosphorylation of A36R occurs only at the plasma membrane, providing an explanation for why actin tails are not formed by cytoplasmic virus particles. Furthermore, phosphorylation of A36R-Y132 depends on phosphorylation of neighbouring Y112, a binding site for the "primary" adaptor Nck. In the second part of the thesis, the mechanism by which vaccinia infection disrupts the centrosome was investigated. Initial work focused on a viral kinase, F10L both in centrosome disruption and in viral morphogenesis. However, the viral phosphatase, H1L was subsequently identified as necessary and sufficient for the centrosome disruption phenotype. Host cell binding-partners of H1L were purified and a process of target verification was begun. AuroraA was also tested as a candidate target, and these experiments suggest that vaccinia infection and H1L-mediated centrosome disruption affect cell cycle progression in different ways.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Subversion of both the actin and microtubule cytoskeletons during vaccinia virus infection
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Vaccinia virus
URI: https://discovery.ucl.ac.uk/id/eprint/10119924
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