Transforming Properties of Beta-3 Human Papillomavirus E6 and E7 Proteins

• Published in: mSphere 2020-08, Vol.5 (4)
• Main Authors: Minoni, Lucia, Romero-Medina, Maria Carmen, Venuti, Assunta, Sirand, Cécilia, Robitaille, Alexis, Altamura, Gennaro, Le Calvez-Kelm, Florence, Viarisio, Daniele, Zanier, Katia, Müller, Martin, Accardi, Rosita, Tommasino, Massimo
• Format: Article
• Language: English
• Subjects: Alphapapillomavirus - classification; Alphapapillomavirus - genetics; Alphapapillomavirus - pathogenicity; Animals; beta-3 and mucosal HPV types; Cancer; Carcinogenesis; Cell cycle; Cells, Cultured; Comparative analysis; Deoxyribonucleic acid; DNA; Epithelial Cells - virology; Epithelium; Gene expression; Genera; Host-Microbe Biology; Human papillomavirus; Human papillomavirus 16 - genetics; Humans; INK4a protein; keratinocyte immortalization; Keratinocytes; Keratinocytes - virology; Life Sciences; Male; Mice; Morphology; Mucosa; Mucous Membrane - cytology; Mucous Membrane - virology; NIH 3T3 Cells; Oncogene Proteins, Viral - genetics; p16 Protein; p53 and pRb regulated pathways; p53 Protein; Papillomaviridae; Papillomavirus E7 Proteins - genetics; Proteasomes; Research Article; Skin; Skin - virology; Skin cancer; Species; Ultraviolet radiation
• ISSN: 2379-5042; 2379-5042
• DOI: 10.1128/msphere.00398-20

The beta human papillomaviruses (HPVs) are subdivided into 5 species (beta-1 to beta-5), and they were first identified in the skin. However, the beta-3 species appears to be more highly represented in the mucosal epithelia than in the skin. Functional studies have also highlighted that beta-3 HPV49 shares some functional similarities with mucosal high-risk (HR) HPV16. Here, we describe the characterization of the transforming properties of the entire beta-3 species, which includes three additional HPV types: HPV75, HPV76, and HPV115. HPV49, HPV75, and HPV76 E6 and E7 (E6/E7), but not HPV115 E6 and E7, efficiently inactivate the p53 and pRb pathways and immortalize or extend the life span of human foreskin keratinocytes (HFKs). As observed for HR HPV16, cell cycle deregulation mediated by beta-3 HPV E6/E7 expression leads to p16 accumulation, whereas no p16 was detected in beta-2 HPV38 E6/E7 HFKs. As shown for HPV49 E6, HPV75 and HPV76 E6s degrade p53 by an E6AP/proteasome-mediated mechanism. Comparative analysis of cellular gene expression patterns of HFKs containing E6 and E7 from HR HPV16, beta-3 HPV types, and beta-2 HPV38 further highlights the functional similarities of HR HPV16 and beta-3 HPV49, HPV75, and HPV76. The expression profiles of these four HPV HFKs show some similarities and diverge substantially from those of beta-3 HPV115 E6/E7 and beta-2 HPV38 E6/E7 HFKs. In summary, our data show that beta-3 HPV types share some mechanisms with HR HPV types and pave the way for additional studies aiming to evaluate their potential role in human pathologies. Human papillomaviruses are currently classified in different genera. Mucosal HPVs belonging to the alpha genus have been clearly associated with carcinogenesis of the mucosal epithelium at different sites. Beta HPV types have been classified as cutaneous. Although findings indicate that some beta HPVs from species 1 and 2 play a role, together with UV irradiation, in skin cancer, very little is known about the transforming properties of most of the beta HPVs. This report shows the transforming activity of E6 and E7 from beta-3 HPV types. Moreover, it highlights that beta-3 HPVs share some biological properties more extensively with mucosal high-risk HPV16 than with beta-2 HPV38. This report provides new paradigms for a better understanding of the biology of the different HPV types and their possible association with lesions at mucosal and/or cutaneous epithelia.