Abdul-Sada, H, Muller, M orcid.org/0000-0002-2878-464X, Mehta, R et al. (4 more authors) (2017) The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-kB by Merkel Polyomavirus small Tumour antigen. Oncotarget, 8 (15). pp. 25418-25432. ISSN 1949-2553
Abstract
Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with a high metastatic potential. The majority of MCC cases are caused by the Merkel cell polyomavirus (MCPyV), through expression of the virus-encoded tumour antigens. Whilst mechanisms attributing tumour antigen expression to transformation are being uncovered, little is known of the mechanisms by which MCPyV persists in the host. We previously identified the MCPyV small T antigen (tAg) as a novel inhibitor of nuclear factor kappa B (NF-B) signalling and a modulator of the host anti-viral response. Here we demonstrate that regulation of NF-B activation involves a previously undocumented interaction between tAg and regulatory sub-unit 1 of protein phosphatase 4 (PP4R1). Formation of a complex with PP4R1 and PP4c is required to bridge MCPyV tAg to the NEMO adaptor protein, allowing deactivation of the NF-B pathway. Mutations in MCPyV tAg that fail to interact with components of this complex, or siRNA depletion of PP4R1, prevents tAg-mediated inhibition of NF-B and pro-inflammatory cytokine production. Comparison of tAg binding partners from other human polyomavirus demonstrates that interactions with NEMO and PP4R1 are unique to MCPyV. Collectively, these data identify PP4R1 as a novel target for virus subversion of the host anti-viral response.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Authors 2017. This is an open access article under the terms of the Creative Commons Attribution 3.0 License. |
Keywords: | virus; skin cancer; NF-κB; immune evasion; phosphatase |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Molecular Biology (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Virology 2 (Leeds) |
Funding Information: | Funder Grant number MRC MR/K012665/1 Kidney Research Fund UK RP25/2013 |
Depositing User: | Symplectic Publications |
Date Deposited: | 09 Feb 2017 10:25 |
Last Modified: | 05 Oct 2017 16:20 |
Published Version: | https://doi.org/10.18632/oncotarget.15836 |
Status: | Published |
Publisher: | Impact Journals |
Identification Number: | 10.18632/oncotarget.15836 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:112139 |