Research Papers:
The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen
Metrics: PDF 2268 views | HTML 4071 views | ?
Abstract
Hussein Abdul-Sada1, Marietta Müller1, Rajni Mehta1, Rachel Toth2, J. Simon C. Arthur2, Adrian Whitehouse1, Andrew Macdonald1
1School of Molecular and Cellular Biology, Faculty of Biological Sciences, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
2Division of Immunology and Cell Signalling and Division of Signal Transduction Therapy College of Life Sciences, University of Dundee, Dundee, UK
Correspondence to:
Andrew Macdonald, email: [email protected]
Keywords: virus, skin cancer, NF-κB, immune evasion, phosphatase
Received: December 15, 2016 Accepted: February 02, 2017 Published: March 02, 2017
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-kB) signalling and a modulator of the host anti-viral response. Here we demonstrate that regulation of NF-kB 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-kB 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-kB 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.
![Creative Commons License](/images/80x15.png)
PII: 15836