Merkel Cell Polyomavirus Small T Antigen Targets the NEMO Adaptor Protein To Disrupt Inflammatory Signaling
David A. Griffiths,Hussein K . Abdul-Sada,Laura M. Knight,Brian R. Jackson,Kathryn H. Richards,Emma L. Prescott,A. Howard S. Peach,G. Eric Blair,Andrew Macdonald,Adrian Whitehouse +9 more
TLDR
A new function of MCPyV small T antigen (ST) is identified as an inhibitor of NF-κB-mediated transcription, allowing establishment of early or persistent infection within the host cell.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.read more
Citations
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The biology and treatment of Merkel cell carcinoma: current understanding and research priorities
Paul W. Harms,Kelly L. Harms,Patrick S. Moore,James A. DeCaprio,Paul Nghiem,Michael K K Wong,Isaac Brownell +6 more
TL;DR: The availability of immune checkpoint inhibition has improved the outcomes of a subset of patients with MCC, although many unmet needs continue to exist, according to this Consensus Statement.
Journal ArticleDOI
Viral Oncology: Molecular Biology and Pathogenesis.
TL;DR: In this review, the molecular biology and oncogenic pathways of established human oncoviruses will be discussed and available and emerging therapies for them will be mentioned.
Journal ArticleDOI
Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: a prospective validation study
Kelly G. Paulson,C. Lewis,Mary W. Redman,William T. Simonson,Aaron Lisberg,Deborah I. Ritter,Chihiro Morishima,Kathleen Hutchinson,Lola Mudgistratova,Astrid Blom,Jayasri G. Iyer,Ata S. Moshiri,Erica S. Tarabadkar,Joseph J. Carter,Shailender Bhatia,Masaoki Kawasumi,Denise A. Galloway,Mark H. Wener,Paul Nghiem +18 more
TL;DR: The present study assesses the clinical utility of MCPyV‐oncoprotein antibody titers for MCC prognostication and surveillance.
Journal ArticleDOI
Merkel cell polyomavirus infection and Merkel cell carcinoma.
TL;DR: A review discusses these recent discoveries on how MCPyV interacts with host cells to achieve persistent infection and, in the immunocompromised population, contributes to MCC development.
Journal ArticleDOI
Large T and small T antigens of Merkel cell polyomavirus
TL;DR: A map of the relevant functional motifs and domains in MCV T antigens that have been identified are provided, highlighting their roles in tumorigenesis.
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