Abstract
Polyomaviruses are a family of small, non-enveloped DNA viruses that can cause severe disease in immunosuppressed individuals. Studies with SV40, a well-studied model polyomavirus, have revealed the role of host proteins in polyomavirus entry and trafficking to the nucleus, in viral transcription and DNA replication, and in cell transformation. In contrast, little is known about host factors or cellular signaling pathways involved in the late steps of productive infection leading to release of progeny polyomaviruses. We previously showed that cytoplasmic vacuolization, a characteristic late cytopathic effect of SV40 infection, depends on the specific interaction between the major viral capsid protein VP1 and its cell surface ganglioside receptor GM1. Here, we show that, late during infection, SV40 activates a signaling cascade in permissive monkey CV-1 cells involving Ras, Rac1, MKK4, and JNK to stimulate SV40-specific cytoplasmic vacuolization and subsequent cell lysis and virus release. Inhibition of individual components of this signaling pathway inhibits vacuolization, lysis, and virus release, even though high-level intracellular virus replication occurs. Identification of this pathway for SV40-induced vacuolization and virus release provides new insights into the late steps of non-enveloped virus infection.
Highlights
IntroductionThe polyomaviruses are small, non-enveloped, double-stranded DNA tumor viruses that include pathogenic human viruses such as BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), and Merkel
The polyomaviruses are small, non-enveloped, double-stranded DNA tumor viruses that include pathogenic human viruses such as BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), and MerkelCell polyomavirus (MCPyV) as well as the extensively studied model viruses, murine polyomavirus and simian virus 40 (SV40)
We recently demonstrated that SV40-induced vacuole formation is triggered by binding of oligomeric
Summary
The polyomaviruses are small, non-enveloped, double-stranded DNA tumor viruses that include pathogenic human viruses such as BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), and Merkel. Cell polyomavirus (MCPyV) as well as the extensively studied model viruses, murine polyomavirus and simian virus 40 (SV40). MCPyV, the most recently discovered human tumor virus, is responsible for most cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. JCPyV is the causative agent of progressive multifocal leukencephalopathy (PML), a rare but usually fatal central nervous system-demyelinating disease in immunocompromised individuals or patients receiving immunomodulatory monoclonal antibody treatment for various disorders [2]. JCPyV and BKPyV infections are common in the human population. These viruses are phylogenetically closely related to SV40, which can cause PML-like brain pathology in immunosuppressed monkeys [3,4]. SV40 serves as a model to study human polyomavirus pathogenesis, including neurological disease
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