Research Article: Merkel cell polyomavirus Tumor antigens expressed in Merkel cell carcinoma function independently of the ubiquitin ligases Fbw7 and β-TrCP

Date Published: January 28, 2019

Publisher: Public Library of Science

Author(s): Kristine N. Dye, Markus Welcker, Bruce E. Clurman, Ann Roman, Denise A. Galloway, Michael J. Imperiale.

http://doi.org/10.1371/journal.ppat.1007543

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.

Partial Text

Merkel cell carcinoma (MCC) is an extremely rare, but aggressive, neuroendocrine skin cancer with an incidence of 0.7 cases/100,000 person-years in the United States, and a less than 45% 5-year survival rate, making MCC almost three times as lethal as melanoma [1, 2]. Although MCC was first described in 1972, it wasn’t until 2008 that a previously undescribed polyomavirus was found to be clonally integrated into 80% of MCC tumors and was thus termed Merkel cell polyomavirus (MCPyV) [3, 4]. MCPyV is a small, circular, dsDNA virus that utilizes alternative splicing of its early region (ER) to generate four ER proteins including the Large Tumor antigen (LT), Small Tumor antigen (ST), 57kT, and Alternate Large-T Open reading frame (ALTO) [5]. However, in MCCs only ST and a truncated form of the LT antigen (LT-t) are expressed. The tumor specific truncation of LT occurs as a consequence of a premature stop codon or deletion in the viral genome downstream of the Rb binding site and before the LT helicase domain [6]. Selection of this truncation is thought to be driven through the prevention of several activities and consequences deleterious for tumorigenesis [7, 8].

Integration and expression of MCPyV T antigens accounts for 80% of MCC cases [4]; therefore, elucidating the mechanisms by which LT-t and ST accomplish transformation and tumorigenesis is paramount for the design of novel therapeutics to treat MCPyV positive MCCs. Furthermore, such insight could also have implications not only for understanding polyomavirus oncogenesis and disease, but also for cellular pathways, homeostasis, and broad disease pathology. MCPyV ST has been shown to increase protein levels of MCPyV LT, LT-t, and several other cellular oncoproteins involved in proliferation, such as c-Myc and cyclin E [17, 30]. This has been proposed to be a consequence of ST sequestration of several ubiquitin ligases, including Fbw7 and β-TrCP, and underlies the proposed mechanisms of ST enhancement of viral replication, and induction of transformation and tumorigenesis (S1C Fig) [12, 17–19].

 

Source:

http://doi.org/10.1371/journal.ppat.1007543

 

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