Merkel cell polyomavirus small T antigen targets the NEMO adaptor protein to disrupt inflammatory signaling

J Virol. 2013 Dec;87(24):13853-67. doi: 10.1128/JVI.02159-13. Epub 2013 Oct 9.

Abstract

Merkel cell carcinoma (MCC) is a highly aggressive nonmelanoma skin cancer arising from epidermal mechanoreceptor Merkel cells. In 2008, a novel human polyomavirus, Merkel cell polyomavirus (MCPyV), was identified and is strongly implicated in MCC pathogenesis. Currently, little is known regarding the virus-host cell interactions which support virus replication and virus-induced mechanisms in cellular transformation and metastasis. Here we identify a new function of MCPyV small T antigen (ST) as an inhibitor of NF-κB-mediated transcription. This effect is due to an interaction between MCPyV ST and the NF-κB essential modulator (NEMO) adaptor protein. MCPyV ST expression inhibits IκB kinase α (IKKα)/IKKβ-mediated IκB phosphorylation, which limits translocation of the NF-κB heterodimer to the nucleus. Regulation of this process involves a previously undescribed interaction between MCPyV ST and the cellular phosphatase subunits, protein phosphatase 4C (PP4C) and/or protein phosphatase 2A (PP2A) Aβ, but not PP2A Aα. Together, these results highlight a novel function of MCPyV ST to subvert the innate immune response, allowing establishment of early or persistent infection within the host cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral, Tumor / genetics
  • Antigens, Viral, Tumor / metabolism*
  • Carcinoma, Merkel Cell / genetics
  • Carcinoma, Merkel Cell / immunology
  • Carcinoma, Merkel Cell / metabolism*
  • Carcinoma, Merkel Cell / virology
  • Cell Line
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / immunology
  • I-kappa B Kinase / metabolism*
  • Immunity, Innate
  • Merkel cell polyomavirus / genetics
  • Merkel cell polyomavirus / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Phosphorylation
  • Polyomavirus Infections / genetics
  • Polyomavirus Infections / immunology
  • Polyomavirus Infections / metabolism*
  • Polyomavirus Infections / virology
  • Protein Binding
  • Tumor Virus Infections / genetics
  • Tumor Virus Infections / immunology
  • Tumor Virus Infections / metabolism*
  • Tumor Virus Infections / virology

Substances

  • Antigens, Viral, Tumor
  • IKBKG protein, human
  • NF-kappa B
  • I-kappa B Kinase