PLOS Pathogens
Public Library of Science (PLoS)
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Merkel cell polyomavirus Tumor antigens expressed in Merkel cell carcinoma function independently of the ubiquitin ligases Fbw7 and β-TrCP
Volume: 15, Issue: 1
DOI 10.1371/journal.ppat.1007543

Highlights

Notes

Abstract

Merkel cell polyomavirus (MCPyV) accounts for 80% of all Merkel cell carcinoma (MCC) cases through expression of two viral oncoproteins: the truncated large T antigen (LT-t) and small T antigen (ST). MCPyV ST is thought to be the main driver of cellular transformation and has also been shown to increase LT protein levels through the activity of its Large-T Stabilization Domain (LSD). The ST LSD was reported to bind and sequester several ubiquitin ligases, including Fbw7 and β-TrCP, and thereby stabilize LT-t and several other Fbw7 targets including c-Myc and cyclin E. Therefore, the ST LSD is thought to contribute to transformation by promoting the accumulation of these oncoproteins. Targets of Fbw7 and β-TrCP contain well-defined, conserved, phospho-degrons. However, as neither MCPyV LT, LT-t nor ST contain the canonical Fbw7 phospho-degron, we sought to further investigate the proposed model of ST stabilization of LT-t and transformation. In this study, we provide several lines of evidence that fail to support a specific interaction between MCPyV T antigens and Fbw7 or β-TrCP by co-immunoprecipitation or functional consequence. Although MCPyV ST does indeed increase LT protein levels through its Large-T Stabilization domain (LSD), this is accomplished independently of Fbw7. Therefore, our study indicates a need for further investigation into the role and mechanism(s) of MCPyV T antigens in viral replication, latency, transformation, and tumorigenesis.

https://www.researchpad.co/tools/openurl?pubtype=article&doi=10.1371/journal.ppat.1007543&title=Merkel cell polyomavirus Tumor antigens expressed in Merkel cell carcinoma function independently of the ubiquitin ligases Fbw7 and β-TrCP&author=&keyword=&subject=Research Article,Research and Analysis Methods,Precipitation Techniques,Immunoprecipitation,Co-Immunoprecipitation,Biology and life sciences,Organisms,Viruses,DNA viruses,Polyomaviruses,Sv40,Biology and Life Sciences,Microbiology,Medical Microbiology,Microbial Pathogens,Viral Pathogens,Polyomaviruses,Sv40,Medicine and Health Sciences,Pathology and Laboratory Medicine,Pathogens,Microbial Pathogens,Viral Pathogens,Polyomaviruses,Sv40,Biology and Life Sciences,Organisms,Viruses,Viral Pathogens,Polyomaviruses,Sv40,Biology and Life Sciences,Biochemistry,Enzymology,Enzymes,Ligases,Ubiquitin Ligases,Biology and Life Sciences,Biochemistry,Proteins,Enzymes,Ligases,Ubiquitin Ligases,Biology and Life Sciences,Molecular Biology,Molecular Biology Techniques,Molecular Probe Techniques,Immunoblotting,Research and Analysis Methods,Molecular Biology Techniques,Molecular Probe Techniques,Immunoblotting,Medicine and Health Sciences,Oncology,Carcinogenesis,Biology and Life Sciences,Biochemistry,Proteins,Protein Domains,Physical Sciences,Chemistry,Chemical Properties,Dimerization,Physical Sciences,Chemistry,Physical Chemistry,Chemical Properties,Dimerization,Physical Sciences,Chemistry,Chemical Compounds,Organic Compounds,Amino Acids,Aliphatic Amino Acids,Alanine,Physical Sciences,Chemistry,Organic Chemistry,Organic Compounds,Amino Acids,Aliphatic Amino Acids,Alanine,Biology and Life Sciences,Biochemistry,Proteins,Amino Acids,Aliphatic Amino Acids,Alanine,