STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle

• DOI: 10.1371/journal.ppat.1006975
• Publication Date: 2018-04-09T13:39:56Z
• Authors: Ethan L. Morgan; Christopher W. Wa...; Lucy Hanson; David Kealy; Ieisha Pentland; Victoria McGuire; Cinzia Scarpini; Nicholas Coleman; J. Simon C. Arthur; Joanna L. Parish; Sally Roberts; Andrew Macdonald
• Keywords: Retinoblastoma protein; Cyclin A; Cyclin B1

Human papillomaviruses (HPV) activate a number of host factors to control their differentiation-dependent life cycles. The transcription factor signal transducer and activator (STAT)-3 is important for cell cycle progression survival in response cytokines growth factors. STAT3 requires phosphorylation on Ser727, addition Tyr705 be transcriptionally active. In this study, we show that essential the HPV undifferentiated differentiated keratinocytes. Primary human keratinocytes containing high-risk HPV18 genomes display enhanced compared normal Expression E6 oncoprotein sufficient induce dual at Ser727 by mechanism requiring Janus kinases members MAPK family. E6-mediated activation induces responsive genes including cyclin D1 Bcl-xL. Silencing protein expression siRNA or inhibition small molecule inhibitors, dominant negative site mutants, results blockade progression. Loss active impairs gene prevents episome maintenance upon differentiation, lack abolishes virus genome amplification late expression. Organotypic raft cultures expressing mutant profound reduction suprabasal hyperplasia, which correlates with loss B1 increased differentiation. Finally, observed positive cervical disease biopsies samples, highlighting role carcinogenesis. summary, our data provides evidence critical cycle.