The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen

Hussein Abdul-Sada, Marietta Müller, Rajni Mehta, Rachel Toth, J. Simon C. Arthur, Adrian Whitehouse, Andrew Macdonald (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
211 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)25418-25432
Number of pages15
JournalOncotarget
Volume8
Issue number15
DOIs
Publication statusPublished - 2 Mar 2017

Keywords

  • Journal article
  • Virus
  • Skin cancer
  • NF-κ B
  • Immune evasion
  • Phosphatase

Fingerprint Dive into the research topics of 'The PP4R1 sub-unit of protein phosphatase PP4 is essential for inhibition of NF-κB by merkel polyomavirus small tumour antigen'. Together they form a unique fingerprint.

Cite this