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Title: The role of endocytic machinery during Vaccinia virus egress and spread
Author: Snetkov, X.
ISNI:       0000 0004 8503 1294
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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During its egress, Vaccinia virus induces a series of events at the plasma membrane of infected cells that ultimately enhance the spread of infection. Immediately following fusion with the plasma membrane, the virus recruits the endocytic adaptor protein, AP-2 and clathrin in an A36-dependent manner. Clathrin recruitment acts to cluster the viral integral membrane protein, A36 underneath the virion to generate a robust signalling platform that recruits the adapters Nck and Grb2 downstream of phosphorylated tyrosines 112/132 respectively. This subsequently results in the recruitment of the WIP:N-WASP complex, which stimulates Arp2/3 complex dependent actin polymerization to propel the virus along the plasma membrane and onto neighbouring uninfected cells. In addition, the virus also promotes Arp2/3 driven actin polymerization via recruitment and activation of the GTPase Cdc42, facilitating its interaction with N-WASP. The ability of the virus to activate Cdc42 is dependent on the RhoGEF Intersectin-1, which is also capable of interacting with AP-2. My studies have sought to investigate the molecular mechanism and role of AP-2 and clathrin recruitment during viral egress. I found that three highly conserved Asn-Pro-Phe (NPF) motifs at the C-terminus of A36 interact directly with the Eps15 Homology (EH) domains of intersectin-1 and Eps-15. A recombinant virus lacking all three NPF motifs (∆NPF) is unable to recruit clathrin, AP-2 or intersectin-1. Besides changes in actin polymerization this virus also has defects in viral release and spread. NPF motifs are conserved endocytic interaction modules that a found in all eukaryotes, however A36 is the first viral protein containing functional NPF motifs to be identified to date.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available