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

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 3; p. 380
• Main Authors: Pham, Alexander M, Ortiz, Luz E, Lukacher, Aron E, Kwun, Hyun Jin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.01.2023; MDPI
• Subjects: Aging; Antigen T (large); Antigens; Antigens, Viral, Tumor - genetics; Cancer; Carcinoma, Merkel Cell - genetics; Carcinoma, Merkel Cell - pathology; Cell cycle; Cell growth; Cells; Cellular Senescence; Dengue fever; Fibroblasts; Genetic aspects; Genome, Viral; Genomes; Genotype & phenotype; Health aspects; Homeostasis; Host-virus relationships; Humans; Infections; large T; Merkel cell polyomavirus; Merkel cell polyomavirus - genetics; Merkel cell polyomavirus - metabolism; Morphology; nucleolar stress response; Nucleoli; p21WAF1; p53; Pathogens; Phenotypes; Phosphorylation; Polyoma virus; Polyomavirus Infections - genetics; Senescence; Severe acute respiratory syndrome coronavirus 2; Skin cancer; Skin Neoplasms - pathology; Statistical significance; Tumor Virus Infections - genetics; Tumor Virus Infections - pathology; Viral infections; Viruses; United States; senescence; genome maintenance; large T; p21WAF1; Merkel cell carcinoma; senolytic; nucleolar stress response; Merkel cell polyomavirus; p53
• ISSN: 2073-4409; 2073-4409
• 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.