Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain.
Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain.
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DOI：
10.3390/cells12030380
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发表时间：
2023-01-20
期刊：
影响因子：
6
通讯作者：
Kwun, Hyun Jin
中科院分区：
文献类型：
--
作者：
Pham, Alexander M.;Ortiz, Luz E.;Lukacher, Aron E.;Kwun, Hyun Jin
关键词：
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。虽然持续衰老似乎有助于细胞通路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尚不清楚。默克尔细胞癌(MCC)是一种由人终生感染默克尔细胞多瘤病毒(MCPyV)引起的侵袭性皮肤癌。在这里，我们证明了MCPyV大T(LT)抗原在人皮肤成纤维细胞中的表达引起了一种新的核仁应激反应，随后是依赖p21的衰老和衰老相关的分泌表型(SASP)，这是MCPyV基因组维持所必需的。衰老处理和Navitoclax治疗导致衰老和MCPyV基因组水平降低，这表明一种潜在的预防MCC的疗法。我们的结果揭示了宿主应激反应在病毒持久性中调节人类多瘤病毒基因组维持的机制，这可能导致对MCC的靶向干预。
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.
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影响因子：
--
作者：
Gelgor A;Gam Ze Letova C;Yegorov Y;Kalt I;Sarid R
通讯作者：
Sarid R
影响因子：
11.2
作者：
Chau, B. Nelson;Diaz, Robert L.;Cleary, Michele A.
通讯作者：
Cleary, Michele A.
影响因子：
8.8
作者：
Gallardo, Paola;Real-Calderon, Paula;Daga, Rafael R.
通讯作者：
Daga, Rafael R.
DOI：
10.1183/13993003.02708-2020
发表时间：
2020-12
期刊：
The European respiratory journal
影响因子：
--
作者：
Kelley WJ;Zemans RL;Goldstein DR
通讯作者：
Goldstein DR
细胞衰老是一种抗病毒防御机制。
影响因子：
4.6
作者：
Baz-Martínez M;Da Silva-Álvarez S;Rodríguez E;Guerra J;El Motiam A;Vidal A;García-Caballero T;González-Barcia M;Sánchez L;Muñoz-Fontela C;Collado M;Rivas C
通讯作者：
Rivas C