Too many cooks in the kitchen: HPV driven carcinogenesis - The result of collaboration or competition?

Abstract

Infection by Human Papillomaviruses accounts for the most widespread sexually transmitted infection worldwide. Clinical presentation of these infections can range from subclinical and asymptomatic to anogenital cancers, with the latter associated with persistent infection over a significant period of time. Of the over 200 isotypes of the human virus identified, a subset of these has been characterized as high-risk due to their ability to induce oncogenesis. At the core of Papillomavirus pathogenesis sits three virally encoded oncoproteins: E5, E6, and E7. In this review we will discuss the respective roles of these proteins and how they contribute to carcinogenesis, evaluating key distinguishing features that separate them from their low-risk counterparts. Furthermore, we will consider the complex relationship between this trio and how their interwoven functional networks underpin the development of cancer.

Keywords: Carcinogenesis; E6; HPV; Oncogenesis; Oncoproteins; Papillomavirus.

Fig. 1

The progression of HPV induced cancer in epithelial tissue. Schematic representation of epithelial tissue reorganization in the development of HPV related cancers. On the left epithelial layers are defined. HPV enters through microabrasions or the junction between the endo- and ecto-cervix establishing low copy number episomal replication in basal cells. As infected cells climb through the stratum of the epithelial tissue, changes in viral protein levels can be viewed on the right side with their corresponding stages of the viral life cycle. Following infection precancerous lesions, graded CINI-III, may progress to invasive cancer as the result of persistent infection over the course of up to 20 years. This transition is marked by a decrease in episomal DNA and an increase of cells containing integrated viral DNA. Created in BioRender. Weimer, K. (2024) https://BioRender.com/z51i407.

Fig. 2

Interactions of hr-HPV E6. The canonical hr-HPV E6 structure is shown with interfaces labelled as follows: LxxLL binding pocket is highlighted in raspberry, the TP53 (p53) binding interface is highlighted in gold, the C-terminal PBM is highlighted in blue, and the remaining E6 surface is shown in grey. In the upper left-hand box, the structure of the tertiary 16E6-p53-E6AP complex is displayed (PDB: 4XR8). The proteasomal degradation of p53 is mediated by this complex. In the lower left-hand box, a diagram of E6 modified by phosphorylation of T156 is shown. This introduces interactions with members of the 14-3-3 family with their potential functions in cancer listed. An affinity scale is represented by a red arrow, indicating the strength of interactions which range from 300 μM–50 μM based on fragmentomic in vitro binding assays although only E6 binding to 14-3-3ζ has been functionally implicated in vivo. To the right interactions with LxxLL partners (top right) and PDZ partners (bottom right) are listed and referred to the LxxLLome and PDZome respectively. Created in BioRender. Weimer, K. (2024) https://BioRender.com/m12c626.