Multiple human polyomaviruses (HPyV) 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 noncanonical 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. Noncanonical 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 ncNF-κB signaling by any polyomavirus and its critical role in MCC tumorigenesis.

中文翻译：

---

Merkel 细胞多瘤病毒小 T 抗原激活非经典 NF-κB 信号以促进肿瘤发生

多种人类多瘤病毒 (HPyV) 可以感染皮肤，但只有默克尔细胞多瘤病毒 (MCPyV) 与癌症默克尔细胞癌 (MCC) 的发展有关。虽然 HPyV6、HPyV7 和 MCPyV 小 T 抗原 (sT) 的表达都诱导了衰老相关的分泌表型 (SASP)，但 MCPyV sT 独特地激活了非经典 NF-κB (ncNF-κB)，而不是经典的 NF-κB 信号，逃避p53介导的细胞衰老。通过其大的 T 稳定域，MCPyV sT 通过诱导 H3K4 三甲基化介导的 NFKB2 和 RELB 转录增加以及通过抑制 FBXW7 促进 NFKB2 稳定和激活来激活 ncNF-κB 信号。SASP 细胞因子分泌需要非经典的 NF-κB 信号传导，它通过自分泌信号促进表达 MCPyV sT 的细胞增殖。病毒阳性 MCC 细胞系和肿瘤显示 ncNF-κB 通路激活和 SASP 基因表达，并且 ncNF-κB 信号传导的抑制阻止了 VP-MCC 细胞在体外和异种移植物中的生长。我们将 MCPyV sT 诱导的 ncNF-κB 信号确定为 MCC 中必不可少的致瘤途径。意义：这项工作是第一个确定任何多瘤病毒对 ncNF-κB 信号传导及其在 MCC 肿瘤发生中的关键作用的工作。