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Modulation of Innate Immune signaling by the small T antigen of Merkel cell polyomavirus – the causative agent of Merkel cell skin cancer

Abdul-Sada, Hussein Katai (2016) Modulation of Innate Immune signaling by the small T antigen of Merkel cell polyomavirus – the causative agent of Merkel cell skin cancer. PhD thesis, University of Leeds.

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Abstract

Merkel cell Polyomavirus (MCPyV) is implicated in the pathogenesis of Merkel cell carcinoma (MCC), a rare and highly aggressive neuroendocrine skin cancer, through expression of two oncoproteins, small T antigen (sT) and large T antigen (LT). MCPyV sT expression is essential for cell transformation, however, the mechanisms by which sT may contribute towards MCC are poorly understood. Studies from our group identified that sT is an antagonist of NF-B signalling (Griffiths et al., 2013). This thesis focuses on dissecting the molecular basis of inhibition. Co-immunoprecipitation and co-immunofluorescence studies demonstrate an interaction between sT and the critical adaptor protein NF-B essential modulator (IKKγ, NEMO) that is necessary for inhibiting NF-B activation. A comprehensive mapping exercise identified the regions in each protein necessary for mediating this interaction. Mechanistically, we reveal that NEMO does not interact with sT directly, rather it forms part of a larger protein complex. Using proteomic data, we establish interactions between sT and novel protein phosphatase proteins including PP4C. In comprehensive studies, we show that a complex of PP4C and the PP4 targeting sub-unit PP4R1 are necessary for bridging sT to NEMO in vitro. In cells, depletion of PP4R1 prevents formation of the sT-NEMO complex and point mutations in sT that prevent binding to these host proteins reduce the ability of sT to impair NF-B driven transcription. Finally, we demonstrate that interactions with PP4R1 and NEMO are not shared with sT proteins from other polyomaviruses tested, implicating potential unique functions for MCPyV sT amongst the Polyomaviridae. This study provides convincing evidence for the molecular mechanisms that MCPyV sT utilises to evade the innate immune system and may help to explain the chronic nature of this virus.

Item Type: Thesis (PhD)
Additional Information: The thesis contains some novel information about the Biological mechanism that Merkel cell polyomavirus can invade the celll and manipulate the NF-kB signaling pathway
Keywords: Merkel cell polyomavirus, NF-kB signaling pathway, merkel cell cancer.
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds) > Institute for Molecular and Cellular Biology (Leeds)
Identification Number/EthosID: uk.bl.ethos.689262
Depositing User: Mr. H. K. Abdul-Sada
Date Deposited: 27 Jun 2016 09:29
Last Modified: 06 Oct 2016 14:43
URI: http://etheses.whiterose.ac.uk/id/eprint/13363

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