Merkel cell polyomavirus large T antigen binding to pRb promotes skin hyperplasia and tumor development

Clear evidence supports a causal link between Merkel cell polyomavirus (MCPyV) and the highly aggressive human skin cancer called Merkel cell carcinoma (MCC). Integration of viral DNA into the human genome facilitates continued expression of the MCPyV small tumor (ST) and large tumor (LT) antigens in virus-positive MCCs. In MCC tumors, MCPyV LT is truncated in a manner that renders the virus unable to replicate yet preserves the LXCXE motif that facilitates its binding to and inactivation of the retinoblastoma tumor suppressor protein (pRb). We previously developed a MCPyV transgenic mouse model in which MCC tumor-derived ST and truncated LT expression were targeted to the stratified epithelium of the skin, causing epithelial hyperplasia, increased proliferation, and spontaneous tumorigenesis. We sought to determine if any of these phenotypes required the association between the truncated MCPyV LT and pRb. Mice were generated in which K14-driven MCPyV ST/LT were expressed in the context of a homozygous Rb-Delta LXCXE knock-in allele that attenuates LT-pRb interactions through LT's LXCXE motif. We found that many of the phenotypes including tumorigenesis that develop in the K14-driven MCPyV transgenic mice were dependent upon LT's LXCXE-dependent interaction with pRb. These findings highlight the importance of the MCPyV LT-pRb interaction in an in vivo model for MCPyV-induced tumorigenesis. Author summaryMerkel cell polyomavirus (MCPyV) causes a highly aggressive form of skin cancer called Merkel cell carcinoma (MCC). In human MCC tumors, two viral proteins are expressed: truncated large T antigen (LT) and small T antigen (ST). It is hypothesized that the interaction between MCPyV LT and a cellular tumor suppressor protein, the retinoblastoma protein (pRb), is involved in MCPyV-associated MCC development. In this study, we found that the LT-pRb interaction promotes hyperplasia, proliferation, and tumor development in the skin of transgenic mice expressing the MCPyV LT and ST antigens. This is the first study to directly interrogate a function of the MCPyV LT in skin and highlights the importance of its specific interaction with the host protein pRb in promoting cutaneous phenotypes. These results not only provide insight into the mechanisms of the individual T antigen oncoproteins that are potentially important during virus-induced human disease, but also advance our understanding of how functions of the MCPyV T antigens potentiate changes in the skin, a proposed site of MCPyV tissue tropism.