默克尔细胞多瘤病毒大 T 抗原通过其独特结构域诱导细胞衰老以实现宿主生长停滞和病毒基因组持续存在。

Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain.

机构信息

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

Penn State Cancer Institute, Hershey, PA 17033, USA.

出版信息

Cells. 2023 Jan 20;12(3):380. doi: 10.3390/cells12030380.

Senescent cells accumulate in the host during the aging process and are associated with age-related pathogeneses, including cancer. Although persistent senescence seems to contribute to many aspects of cellular pathways and homeostasis, the role of senescence in virus-induced human cancer is not well understood. Merkel cell carcinoma (MCC) is an aggressive skin cancer induced by a life-long human infection of Merkel cell polyomavirus (MCPyV). Here, we show that MCPyV large T (LT) antigen expression in human skin fibroblasts causes a novel nucleolar stress response, followed by p21-dependent senescence and senescence-associated secretory phenotypes (SASPs), which are required for MCPyV genome maintenance. Senolytic and navitoclax treatments result in decreased senescence and MCPyV genome levels, suggesting a potential therapeutic for MCC prevention. Our results uncover the mechanism of a host stress response regulating human polyomavirus genome maintenance in viral persistency, which may lead to targeted intervention for MCC.

衰老细胞在衰老过程中在宿主体内积累，并与年龄相关的发病机制有关，包括癌症。尽管持续的衰老似乎有助于细胞途径和体内平衡的许多方面，但衰老在病毒诱导的人类癌症中的作用还不是很清楚。 Merkel 细胞癌（MCC）是一种由 Merkel 细胞多瘤病毒（MCPyV）的终生人类感染引起的侵袭性皮肤癌。在这里，我们表明，人皮肤成纤维细胞中 MCPyV 大 T（LT）抗原的表达会引起新型核仁应激反应，随后是 p21 依赖性衰老和衰老相关分泌表型（SASPs），这对于 MCPyV 基因组的维持是必需的。衰老细胞溶解剂和 navitoclax 的治疗会导致衰老和 MCPyV 基因组水平的降低，这表明 MCC 预防的一种潜在治疗方法。我们的研究结果揭示了宿主应激反应调节人类多瘤病毒基因组维持在病毒持续性中的机制，这可能为 MCC 的靶向干预提供了依据。