Large T and small T antigens of Merkel cell polyomavirus

Abstract

Merkel cell polyomavirus (MCV) is the etiological agent of Merkel cell carcinoma (MCC), a rare and highly lethal human skin cancer. A natural component of skin flora, MCV becomes tumorigenic only after integration into the host DNA together with specific mutations to the viral genome. Research on MCV large T (LT) and small T (sT) antigens, the only viral products expressed in MCC, shows that these major oncoproteins not only possess biochemical functions found in common with other polyomavirus T antigens, but also demonstrate new cellular targets not described in previous polyomavirus models. This review provides a map of the relevant functional motifs and domains in MCV T antigens that have been identified, highlighting their roles in tumorigenesis.

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…While it appears that the LXCXE motif is critical for MCPyV-driven oncogenesis, mutation of LT resulting in C-terminal truncation is another crucial event in MCC tumor development. This hallmark truncation event within MCCs eliminates uncontrolled viral replication, as is seen in other virally-driven cancers, thereby preventing initiation of DNA damage response and cell death [12,20].…”

“…MCPyV is a small (∼5 kb), double stranded DNA virus that consists of both early and late gene regions [20]. [20].…”

“…[20]. Current evidence suggests that LT and sT are the major oncoproteins mediating MCPyV-driven tumorigenesis as knockdown of these T antigens results in cell cycle arrest and death in MCPyV-positive MCC cell lines [21][22][23].…”

“…Rb normally sequesters the transcription factor E2F, however, LT binding to Rb releases E2F resulting in increased expression of cyclin E and CDK2. This promotes entry into the S-phase of the cell cycle and subsequent cellular proliferation [20]. While it appears that the LXCXE motif is critical for MCPyV-driven oncogenesis, mutation of LT resulting in C-terminal truncation is another crucial event in MCC tumor development.…”

“…MCPyV sT alters cap-dependent translation through inhibition of 4E-BP1 and can prevent degradation of MCPyV LT as well as other key oncoproteins including cyclin E, c-Myc, c-Jun, Notch, mTOR, MCL-2 and NF-κB2 through suppression of the E3 ubiquitin ligase, SCF Fbw7 [29]. Detailed summaries of the currently known functions of LT and sT are presented in several recent reviews [20,30]. Importantly, these viral oncoproteins are persistently expressed in MCC tumors ( Figure 1D) and are absent in normal tissues, thereby providing ideal targets for immune therapy.…”