Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain.
Merkel cell carcinoma
Merkel cell polyomavirus
genome maintenance
large T
nucleolar stress response
p21WAF1
p53
senescence
senolytic
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
20 01 2023
20 01 2023
Historique:
received:
28
11
2022
revised:
13
01
2023
accepted:
17
01
2023
entrez:
11
2
2023
pubmed:
12
2
2023
medline:
15
2
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36766726
pii: cells12030380
doi: 10.3390/cells12030380
pmc: PMC9913222
pii:
doi:
Substances chimiques
Antigens, Viral, Tumor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINDS NIH HHS
ID : R35 NS127217
Pays : United States
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