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Article

Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth

1
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
2
Penn State Cancer Institute, Hershey, PA 17033, USA
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(9), 1043; https://doi.org/10.3390/v12091043
Submission received: 27 August 2020 / Revised: 14 September 2020 / Accepted: 16 September 2020 / Published: 18 September 2020
(This article belongs to the Special Issue Polyomaviruses)

Abstract

Merkel cell polyomavirus (MCV) is the only known human oncogenic virus in the polyomaviridae family and the etiological agent of most Merkel cell carcinomas (MCC). MCC is an aggressive and highly metastatic skin cancer with a propensity for recurrence and poor prognosis. Large tumor antigen (LT), is an essential oncoprotein for MCV transcription, viral replication, and cancer cell proliferation. MCV LT is a short-lived protein that encodes a unique domain: MCV LT unique regions (MURs). These domains consist of phosphorylation sites that interact with multiple E3 ligases, thus limiting LT expression and consequently, viral replication. In this study, we show that MURs are necessary for regulating LT stability via multiple E3 ligase interactions, resulting in cell growth arrest. While expression of wild-type MCV LT induced a decrease in cellular proliferation, deletion of the MUR domains resulted in increased LT stability and cell proliferation. Conversely, addition of MURs to SV40 LT propagated E3 ligase interactions, which in turn, reduced SV40 LT stability and decreased cell growth activity. Our results demonstrate that compared to other human polyomaviruses (HPyVs), MCV LT has evolved to acquire the MUR domains that are essential for MCV LT autoregulation, potentially leading to viral latency and MCC.
Keywords: Merkel cell carcinoma; skin cancer; Merkel cell polyomavirus; Large T antigen; cell proliferation; E3 ligases; protein stability; viral latency; MCV LT unique regions Merkel cell carcinoma; skin cancer; Merkel cell polyomavirus; Large T antigen; cell proliferation; E3 ligases; protein stability; viral latency; MCV LT unique regions

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MDPI and ACS Style

Nwogu, N.; Ortiz, L.E.; Kwun, H.J. Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth. Viruses 2020, 12, 1043. https://doi.org/10.3390/v12091043

AMA Style

Nwogu N, Ortiz LE, Kwun HJ. Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth. Viruses. 2020; 12(9):1043. https://doi.org/10.3390/v12091043

Chicago/Turabian Style

Nwogu, Nnenna, Luz E. Ortiz, and Hyun Jin Kwun. 2020. "Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth" Viruses 12, no. 9: 1043. https://doi.org/10.3390/v12091043

APA Style

Nwogu, N., Ortiz, L. E., & Kwun, H. J. (2020). Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth. Viruses, 12(9), 1043. https://doi.org/10.3390/v12091043

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