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)/IKKß-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) Aß, 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.
Subject(s)
Antigens, Viral, Tumor/metabolism , Carcinoma, Merkel Cell/metabolism , I-kappa B Kinase/metabolism , Merkel cell polyomavirus/metabolism , Polyomavirus Infections/metabolism , Tumor Virus Infections/metabolism , Antigens, Viral, Tumor/genetics , Carcinoma, Merkel Cell/genetics , Carcinoma, Merkel Cell/immunology , Carcinoma, Merkel Cell/virology , Cell Line , Humans , I-kappa B Kinase/genetics , I-kappa B Kinase/immunology , Immunity, Innate , Merkel cell polyomavirus/genetics , NF-kappa B/genetics , NF-kappa B/immunology , Phosphorylation , Polyomavirus Infections/genetics , Polyomavirus Infections/immunology , Polyomavirus Infections/virology , Protein Binding , Tumor Virus Infections/genetics , Tumor Virus Infections/immunology , Tumor Virus Infections/virologyABSTRACT
The optimal treatment for type II endoleaks remains unclear. The present report describes a case of ischemic skin ulceration after glue embolization of a type II endoleak with challenging access in a multiply comorbid 82-year-old woman with an expanding aneurysm sac 3 years after endovascular aneurysm repair. Embolization was performed from a proximal position with an n-butyl cyanoacrylate/Ethiodol mixture to allow flow into the endoleak because direct sac puncture was hazardous. One week after intervention, an eschar, which progressed to superficial necrosis as a result of partial nontarget delivery of sclerosant, developed over the left iliac crest. The eschar was self-limiting, with complete resolution by 6 months.
