Merkel Cell Polyomavirus Small T Antigen Activates Non-Canonical NF-κB Signaling to Promote Tumorigenesis.

Multiple human polyomaviruses (HPyVs) can infect the skin, but only Merkel Cell Polyomavirus (MCPyV) has been implicated in the development of a cancer, Merkel Cell Carcinoma (MCC). While expression of HPyV6, HPyV7, and MCPyV small T antigens (sT) all induced a senescence associated secretory phenotype (SASP), MCPyV sT uniquely activated non-canonical NF-κB (ncNF-κB), instead of canonical NF-κB signaling, to evade p53-mediated cellular senescence. Through its large T stabilization domain, MCPyV sT activated ncNF-κB signaling both by inducing H3K4 trimethylation-mediated increases of NFKB2 and RELB transcription and also by promoting NFKB2 stabilization and activation through FBXW7 inhibition. Non-canonical NF-κB signaling was required for SASP cytokine secretion, which promoted the proliferation of MCPyV sT expressing cells through autocrine signaling. Virus-positive MCC cell lines and tumors showed ncNF-κB pathway activation and SASP gene expression, and the inhibition of ncNF-κB signaling prevented VP-MCC cell growth in vitro and in xenografts. We identify MCPyV sT induced ncNF-κB signaling as an essential tumorigenic pathway in MCC. Implications: This work is the first to identify the activation of non-canonical NF-κB (ncNF-κB) signaling by any polyomavirus and its critical role in MCC tumorigenesis.