Laskey, P.; (2007) The interaction between the HPV E1^E4 protein and the cell cytoskeleton. Doctoral thesis , University of London.

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Abstract

Papillomaviruses are small DNA viruses, which cause benign and malignant lesions in the differentiated epithelium of mammals and birds. A small subset of human papillomaviruses (HPV's), have been identified as the etiological agent of cervical cancer, with HPV 16 being found in over half of all cases. The HPV 16 E1AE4 protein is expressed late in the virus lifecycle. The protein can induce cell cycle arrest through an interaction with CyclinB/Cdk, and this is thought to facilitate viral genome amplification. E1AE4 can also associate with the cytokeratin network leading to its collapse, although this function is poorly understood. The work described in this thesis shows that ElAE4s ability to bind to keratins is conserved amongst different members of the a HPV group, and to a lesser extent amongst members of the more distantly related y-group. When expressed in SiHa cervical epithelial cells, 16 E1AE4 induced the collapse of affected keratin 8/18 network, and lead to the formation of Mallory body-like structures. Western blotting and immuno-precipitation revealed that the ElAE4/keratin association results in keratin phosphorylation and ubiquitination. 16 E1AE4 increases in abundance towards the epithelial surface, and coincides with keratin disruption in the upper epithelial layers. Immuno-fluorescence and biochemical analysis of HPV 2 and 16 lesions support the idea that keratin phosphorylation and ubiquitination may also occur in vivo. An effect of 16 E1AE4 on keratin dynamics was apparent when YFP-16E1AE4 was followed in monolayer cells by time-lapse microscopy. Although filament polymerisation and migration are not necessarily disrupted by 16 E1AE4, it appears that the progressive accumulation of E1AE4 can lead to filament stabilization, and eventually to keratin network disruption.

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