SV40 polyomavirus activates the Ras-MAPK signaling pathway for vacuolization, cell death, and virus release

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, viral transcription and DNA replication, and cell transformation. In contrast, little is known about host factors or cellular signaling pathways involved in the late steps of productive infection leading to polyomavirus release. We previously showed that cytoplasmic vacuolization, a characteristic late cytopathic effect of SV40, 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 CV-1 monkey cells involving Ras, Rac1, MKK4 and JNK to induce 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. The identification of this pathway for SV40-induced vacuolization and virus release provides new insights into the late steps of non-enveloped virus infection and reveals potential drug targets for the treatment of diseases caused by these viruses.\n\nIMPORTANCEThe polyomaviruses are small DNA viruses that include important model viruses and human pathogens that can cause fatal disease, including cancer, in immunosuppressed individuals. There are no vaccines or specific antiviral agents for any polyomavirus. Here, we show that late during infection, SV40 activates a signaling cascade involving Ras, Rac, and JNK that is required for cytoplasmic vacuolization and efficient virus release. This pathway may represent a new point of intervention to control infection by these viruses.